Oxygenated amino- or ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives and their medical use

ABSTRACT

The present invention relates to oxygenated amino or ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives, in particular the compounds of formula 1, 2, 3, 4, 5 or 6, and their medical use, including their use in the treatment, prevention or amelioration of an inflammatory, autoimmune and/or allergic disorder, or a proliferative, neoplastic or dysplastic disease or disorder.

The present invention relates to oxygenated amino or ammonium-containingsulfonic acid, phosphonic acid and carboxylic acid derivatives, inparticular the compounds of formula 1, 2, 3, 4, 5 or 6, and theirmedical use, including their use in the treatment, prevention oramelioration of an inflammatory, autoimmune and/or allergic disorder, ora proliferative, neoplastic or dysplastic disease or disorder.

Without being bound by theory, the compounds provided herein areconsidered to exert their pharmacological activity through inhibition ofthe phosphoinositide 3-kinase (PI3K)/Akt kinase pathway. Theserine/threonine protein kinase Akt (also known as Protein Kinase B) isa key mediator of signal transduction. Akt is activated by numerousreceptors, including those of growth factors, cytokines, hormones andinsulin as well as by the attachment of cells to the extracellularmatrix. Once activated, the plasma membrane receptors stimulate theactivity of PI3K to generate phosphatidylinositol-3,4,5-trisphosphate(PIP3), a lipid second messenger essential for the translocation of Akt,which contains a PIP3-binding pleckstrin homology (PH)-domain, from thecytoplasm to the plasma membrane (Franke et al., Cell 81:727-736,(1995)). Once recruited to the membrane, it is phosphorylated andactivated by other kinases (Hemmings, Science 275:628-630 (1997);Hemmings, Science 276:534 (1997); Downward, Science 279:673-674 (1998);Alessi et al., EMBO J. 15:6541-6551 (1996)), such as PDK1 and mTORC2.

Akt in turn is responsible for regulating the function of many cellularproteins involved in processes such as transcription, cell proliferationand apoptosis (programmed cell death), angiogenesis, cell motility andglucose metabolism (Kulik et al., Mol Cell Biol. 17:1595-1606 (1997);Franke et al., Cell 88:435-437 (1997); Kaufmann-Zeh et al., Nature385:544-548 (1997); Hemmings, Science 275:628-630 (1997); Dudek et al.,Science 275:661-665 (1997)). Activated PI3K/Akt pathway protects cellsfrom apoptosis and by acting as a modulator of anti-apoptotic signallingin tumor cells, Akt is a target for cancer therapy. Blocking thePI3K/Akt pathway could therefore simultaneously inhibit theproliferation of tumor cells and sensitize towards pro-apoptotic agents(Falasca, Curr Pharm Des. 16:1410-6 (2010)).

These findings indicate that Akt may be a drug target for the treatmentof inflammation, autoimmune diseases and allergy as well as cancer.Accordingly, the compounds provided herein, in particular the compoundsof formula 1, 2, 3, 4, 5 or 6, are useful in the treatment, preventionor amelioration of such illnesses.

Broad-acting immunomodulatory drugs such as corticosteroids, calcineurininhibitors and cyclosporin are highly effective and have been used forthe therapy of allergic and cellular inflammatory diseases, includingautoimmune diseases, for many years. They are potent in suppressing bothTh1 and Th2 driven processes, yet they suffer from undesirableside-effects, which limit their therapeutic window. Corticosteroidsregulate the expression of numerous genes and, consequently, their useis limited by severe adverse effects. Typical serious adverse effects ofshort-term corticosteroids use are disturbances in water and saltretention, lipid metabolism, skin thinning and changes in behaviour.More serious adverse effects associated with long-term systemic exposureto corticosteroids include increased appetite and weight gain, depositsof fat in chest, face, upper back, and stomach, water and salt retentionleading to swelling and edema, high blood pressure, diabetes, slowedhealing of wounds, osteoporosis, cataracts, acne, muscle weakness,thinning of the skin, increased susceptibility to infection, stomachulcers, increased sweating, mood swings, psychological problems such asdepression, adrenal suppression and crisis.

More specifically targeted therapeutics, such as biologics, e.g.,Antibodies against Certain cytokines or their receptors, inhibit asingle protein target and are effective in certain situations, but onlyaddress one of the targets in a highly redundant inflammatory cascadeand are hence often used in combination therapy, as effective resolutionof inflammatory diseases requires several targets to be addressedsimultaneously.

There is a high unmet medical need for new drugs that curb theunderlying disease processes. For instance, in rheumatoid arthritis (RA)such disease-modifying antirheumatic drugs (DMARDs) can slow downprogressive joint destruction reducing long-term disease severity. Thisprovides both therapeutic and economic advantages by shortening thetherapeutic period and reducing the dose of concomitant medications.

Many chronic inflammatory diseases, including autoimmune diseases suchas rheumatoid arthritis (RA), are associated with deregulatedintracellular signal transduction pathways, including thephosphoinositide 3-kinase (PI3K)/Akt kinase pathway, and the resultantpathogenic interactions between immune and connective tissue stromalcells lead to changes in cell activation, proliferation, migratorycapacity, and cell survival that contribute to inflammation (Tas et al.,Curr Pharm Des. 11:581-611 (2005)). For example, abnormal functioning,differentiation and/or activation of T-cells, B-cells and myeloid cellshave been documented in various autoimmune diseases, includingrheumatoid arthritis (RA), diabetes mellitus, lupus and multiplesclerosis and studies have detailed anomalous activation of the Aktsignalling axis in the context of systemic autoimmunity (Wu et al.,Disord Drug Targets. 9:145-50 (2009)).

Akt is an important signal transduction pathway mediating the delay ofneutrophil apoptosis by inflammatory mediators, during neutrophilactivation, during inflammation (Rane and Klein, Front Biosci.14:2400-12 (2009)) and control over neutrophil and macrophage migrationand apoptosis is a key factor in the pathogenesis of the majority ofchronic inflammatory diseases.

RA is a chronic inflammatory disease, which results in inflammation ofthe synovial lining and destruction of the adjacent bone and cartilage.Synovial macrophages, fibroblasts and lymphocytes are critical to thepathogenesis of this disease, in which apoptosis plays divergent roles.Signaling pathways, such as PI3K/Akt, are highly activated in the RAjoint, contributing to the expression of aenes that cause inflammationand destruction and expression of a variety of anti-apoptotic molecules.Induction of apoptosis of macrophages, synovial fibroblasts orlymphocytes, through inhibition of the expression of anti-apoptoticmolecules, could be therapeutically beneficial in RA (Liu and Pope, CurrOpin Pharmacol. 3:317-22 (2003)). Furthermore, results suggest thatsignal transduction pathways dependent on PI3K/Akt are involved in theoverproduction of the key inflammatory cytokine IL-17 in patients withrheumatoid arthritis (Kim et al., Arthritis Res Ther. 7:R139-148(2005)).

Akt is closely associated with key membrane-bound receptors andrepresents a convergent integration point for multiple stimuliimplicated in COPD pathogenesis. Akt is also implicated in the systemicmanifestations of COPD such as skeletal muscle wasting and metabolicdisturbances. As such, Akt represents a particularly attractivetherapeutic target for the treatment of COPD (Bozinovski et al., Int JChron Obstruct Pulmon Dis. 1:31-38 (2006)).

The compounds provided herein are positioned to be disease-modifyingdrugs. The compounds have potential for application in a wide variety ofchronic inflammatory indications and in combination with a favorabletolerability, the products can be expected to gain adoption by asignificant number of patients suffering from the severe side effects ofcurrent treatments. Furthermore, the compounds provided herein will besuitable not only for monotherapy but also in combination with existingtherapies, which address specific disease targets but are not sufficientto resolve the disease alone.

WO 2007/071402 describes the use of certain inner ionic phospholipids,phosphonolipids and phosphate derivatives for the treatment orprevention of allergic diseases.

Furthermore, specific quaternary ammonium compounds are disclosed inU.S. Pat. No. 5,545,667 and U.S. Pat. No. 6,136,857 to be useful asantineoplastic agents. These compounds comprise a specific unsubstitutedalkylene group connecting a terminal acid group to the quaternarynitrogen atom and are thus different from the compounds of the inventionwhich comprise, inter alia, an alkylene (R⁴) substituted with anoxygen-containing group. Coy E A et al. Int J Immunopharmacol. 1990;12(8):871-81 report a generalized antiproliferative activity of specificamphiphilic molecules on T-lymphocytes and on a variety of tumor celllines and a lack of specificity for the immune system. WO 2009/136396relates to certain sulfobetaines to be used in the treatment of cancer,obesity, age-related macular degeneration and neurodegenerativediseases. WO 92/16201 relates to the use of specific betaine compoundsfor the treatment of certain viral infections. Yan L, et al. Bioorg MedChem Lett. 2004; 14(19):4861-6 describe certain aminopropyl-phosphonicacid derivatives as agonists of sphingosine-1-phosphate Gprotein-coupled receptors. In WO 2005/000288, specificaminoalkyl-sulfonic acid compounds are disclosed for the treatment ofprotein Aggregation disorders. Further specific quaternary ammoniumcompounds are, for example, disclosed in: Ernst R et al. Toxicology.1980; 15(3):233-42; Speijers G J et al. Vaccine. 1989; 7(4):364-8; VianL et al. Toxic in Vitro. 1995; 9(2):185-190; Parris N, et al. Journal ofthe American Oil Chemists' Society. 1973; 50(12):509-512; Germanaud L,et al. Bulletin de la Société Chimique de France. 1988; 4:699-704; EP0569028 A; JP 2010-120998 A; U.S. Pat. No. 3,432,408; U.S. Pat. No.4,085,134; U.S. Pat. No. 6,004,771; and CN 101456810 A.

It has surprisingly been found that the compounds of the presentinvention, in particular the compounds of formula 1, 2, 3, 4, 5 or 6 asdescribed and defined herein below, have an advantageously lowcytotoxicity. The present invention thus solves the problem of providingtherapeutic agents having a favorable toxicity profile which areeffective, inter alia, in the treatment, prevention or amelioration ofinflammatory, autoimmune and/or allergic disorders.

Accordingly, the present invention provides a compound of the followingformula 1

or a pharmaceutically acceptable salt, solvate or prodrug thereoffor use in the treatment, prevention or amelioration of an inflammatory,autoimmune and/or allergic disorder which is selected from psoriasis,atopic dermatitis (atopic eczema), contact dermatitis, xerotic eczema,seborrheic dermatitis, neurodermitis, dyshidrosis, discoid eczema,venous eczema, dermatitis herpetiformis (Duhring's Disease),autoeczematization, dermatomyositis, hyper-IgE (Buckley) syndrome,Wiskott-Aldrich syndrome, anaphylaxis, food allergy, allergic reactionsto venomous stings, acute urticarias, chronic urticarias, physicalurticarias including aquagenic urticaria, cholinergic urticaria, coldurticaria (chronic cold urticaria), delayed pressure urticaria,dermatographic urticaria, heat urticaria, solar urticaria, vibrationurticaria, adrenergic urticaria, urticaria angioedema, inflammatorybowel disease, Crohn's disease, ulcerative colitis, collagenous colitis,lymphocytic colitis, diversion colitis (diverticulitis), Behçet'ssyndrome, indeterminate colitis, celiac disease, irritable bowelsyndrome, post-operative ileus, eosinophilic gastroenteropathy,gastritis, chronic allergic rhinitic, seasonal allergic rhinitis(hay-fever), allergic conjunctivitis, chemical conjunctivitis, neonatalconjunctivitis, Sjögren syndrome, open-angle glaucoma, dry eye disease(DED; including, e.g., aqueous tear-deficient dry eye (ADDE), Sjögrensyndrome dry eye (SSDE), non-SSDE, or evaporative dry eye (EDE)),diabetic macular edema (or diabetic retinopathy), chronic obstructivepulmonary disease (COPD), allergic asthma, allergic bronchopulmonaryaspergillosis, hypersensitivity pneumonitis, lung fibrosis, rheumatoidarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis,systemic lupus erythematosus (SLE), scleroderma, reactive arthritis,polymyalgia rheumatica, Guillain-Barre syndrome, Hashimoto'sthyroiditis, Grave's disease, temporal arteritis, primary biliarycirrhosis, sclerosing cholangitis, autoimmune hepatitis, alopeciaareata, a graft-versus-host disease, a host-versus-graft disease, or atransplant rejection.

In formula 1, R¹ is a C₁₀₋₂₀ hydrocarbon group.

R² is a C₁₋₄ alkyl group, and R³ is —H, a C₁₋₄ alkyl group or R³ isabsent.

Alternatively, R² and R³ are mutually linked to form a pyrrolidine ring,a piperidine ring or an azepane ring together with the nitrogen atom Xto which they are attached, wherein said pyrrolidine ring, saidpiperidine ring or said azepane ring is optionally substituted with oneor more groups independently selected from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃alkyl)(C₁₋₃ alkyl).

R⁴ is a C₃₋₆ alkylene group which is substituted with one or more groupsindependently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl),—O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl),—O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH.

R⁵ is —SO₃—, —SO₃H, —PO₃H—, —PO₃ ²⁻, —PO₃H₂, —PO₂(OC₁₋₃ alkyl)⁻,—PO₂H(OC₁₋₃ alkyl), —PO(OC₁₋₃ alkyl)₂, —CO₂ ⁻, —CO₂H or —CO₂(C₁₋₃alkyl).

X is N⁺ or, if R³ is absent, X is N.

The present invention also relates to a pharmaceutical compositioncomprising a compound of formula 1, as described and defined herein, ora pharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient for use in the treatment,prevention or amelioration of an inflammatory, autoimmune and/orallergic disorder which is selected from psoriasis, atopic dermatitis(atopic eczema), contact dermatitis, xerotic eczema, seborrheicdermatitis, neurodermitis, dyshidrosis, discoid eczema, vennus eczema,dermatitis herpetiformis (Duhring's Disease), autoeczematization,dermatomyositis, hyper-IgE (Buckley) syndrome, Wiskott-Aldrich syndrome,anaphylaxis, food allergy, allergic reactions to venomous stings, acuteurticarias, chronic urticarias, physical urticarias including aquagenicurticaria, cholinergic urticaria, cold urticaria (chronic coldurticaria), delayed pressure urticaria, dermatographic urticaria, heaturticaria, solar urticaria, vibration urticaria, adrenergic urticaria,urticaria angioedema, inflammatory bowel disease, Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, diversioncolitis (diverticulitis), Behçet's syndrome, indeterminate colitis,celiac disease, irritable bowel syndrome, post-operative ileus,eosinophilic gastroenteropathy, gastritis, chronic allergic rhinitis,seasonal allergic rhinitis (hay-fever), allergic conjunctivitis,chemical conjunctivitis, neonatal conjunctivitis, Sjögren syndrome,open-angle glaucoma, dry eye disease (DED; including, e.g., aqueoustear-deficient dry eye (ADDE), Sjögren syndrome dry eye (SSDE),non-SSDE, or evaporative dry eye (EDE)), diabetic macular edema (ordiabetic retinopathy), chronic obstructive pulmonary disease (COPD),allergic asthma, allergic bronchopulmonary aspergillosis,hypersensitivity pneumonitis, lung fibrosis, rheumatoid arthritis,juvenile rheumatoid arthritis, ankylosing spondylitis, systemic lupuserythematosus (SLE), scleroderma, reactive arthritis, polymyalgiarheumatica, Guillain-Barre syndrome, Hashimoto's thyroiditis, Grave'sdisease, temporal arteritis, primary biliary cirrhosis, sclerosingcholangitis, autoimmune hepatitis, alopecia areata, a graft-versus-hostdisease, a host-versus-graft disease, or a transplant rejection.

The present invention further relates to a method of treating,preventing or ameliorating an inflammatory, autoimmune and/or allergicdisorder, the method comprising the administration of a compound offormula 1, as described and defined herein, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, or a pharmaceuticalcomposition comprising any of the aforementioned entities and apharmaceutically acceptable excipient, to a subject (preferably, a humanor a non-human mammal) in need of such a treatment, prevention oramelioration, wherein the inflammatory, autoimmune and/or allergicdisorder is selected from psoriasis, atopic dermatitis (atopic eczema),contact dermatitis, xerotic eczema, seborrheic dermatitis,neurodermitis, dyshidrosis, discoid eczema, venous eczema, dermatitisherpetiformis (Duhring's Disease), autoeczematization, dermatomyositis,hyper-IgE (Buckley) syndrome, Wiskott-Aldrich syndrome, anaphylaxis,food allergy, allergic reactions to venomous stings, acute urticarias,chronic urticarias, physical urticarias including aquagenic urticaria,cholinergic urticaria, cold urticaria (chronic cold urticaria), delayedpressure urticaria, dermatographic urticaria, heat urticaria, solarurticaria, vibration urticaria, adrenergic urticaria, urticariaangioedema, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, diversion colitis(diverticulitis), Behçet's syndrome, indeterminate colitis, celiacdisease, irritable bowel syndrome, post-operative ileus, eosinophilicgastroenteropathy, gastritis, chronic allergic rhinitis, seasonalallergic rhinitis (hay-fever), allergic conjunctivitis, chemicalconjunctivitis, neonatal conjunctivitis, Sjögren syndrome, open-angleglaucoma, dry eye disease (DED; including, e.g., aqueous tear-deficientdry eye (ADDE), Sjögren syndrome dry eye (SSDE), non-SSDE, orevaporative dry eye (EDE)), diabetic macular edema (or diabeticretinopathy), chronic obstructive pulmonary disease (COPD), allergicasthma, allergic bronchopulmonary aspergillosis, hypersensitivitypneumonitis, lung fibrosis, rheumatoid arthritis, juvenile rheumatoidarthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE),scleroderma, reactive arthritis, polymyalgia rheumatica, Guillain-Barresyndrome, Hashimoto's thyroiditis, Grave's disease, temporal arteritis,primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis,alopecia areata, a graft-versus-host disease, a host-versus-graftdisease, or a transplant rejection.

Allergic and inflammatory responses are characterized by dynamicinteractions of immune and non-immune cells, coordinated throughcell-cell contact and soluble immune mediators. These responses andtheir outcomes are further modified by each individual's genetics andlifestyle.

T helper cells play a key role in initiation and maintenance ofinflammatory responses and can be divided into Th1 (cell-mediatedimmunity) and Th2 (antibody-mediated immunity) driven processes.Imbalances in these responses can result in pathological hyper- orhyposensitivity to antigens. A chronic inflammation manifests in diversedisease states such as, for instance, inflammatory bowel disease,rheumatoid arthritis, atopic dermatitis, urticaria and psoriasis.

Inflammatory responses to antigens can take the form of helper T celldriven responses of different types. Th1 cells mediate cellularresponses involving cytotoxic cells such as macrophages, neutrophils andeosinophils, whereas Th2 cells mediate humoral responses involvingsecretion of antibodies from B cells and activation of mast cells. Othernon-immune responses, such as those involving cyclooxygenase andlipoxygenase may also be involved. Uncontrolled release of cytokines andchemokines is at the heart of inflammatory diseases, like inflammatorybowel disease, rheumatoid arthritis, atopic dermatitis, urticaria andpsoriasis.

A new interventional strategy is provided by the compounds according tothe present invention, in particular the compounds of formula 1, 2, 3,4, 5 or 6 as described and defined herein, which broadly modulate theactivities of proteins within the inflammatory cascade. Throughenrichment of the drug in membrane domains, an allosteric inhibition isexerted on key target proteins in signal transduction cascades ininflammation.

The compounds of the present invention were identified as potentinhibitors of immune mediator release in vitro in a mast cells model, asalso demonstrated in Example 6. Furthermore, they inhibited release ofthe proinflammatory cytokines, TNF-α and interleukin-6, from peripheralblood mononuclear cells (PBMCs) stimulated with lipopolysaccharide,demonstrating immunomodulatory activity in different cell types.

Broad anti-inflammatory activity was confirmed in animal models of Th1and Th2 driven inflammation. In a predominantly Th1-driven delayed typehypersensitivity (DTH) model in mice, the compounds suppressed theinflammatory response to an extent equivalent to dexamethasone, amarketed corticosteroid characterized by severe side effects, as shownin Example 8. In a predominantly Th2 driven allergic contact dermatitismodel, the compounds were highly active after topical application andalso showed an anti-inflammatory effect after oral administration, asshown in Example 9.

In the context of the present invention, it was surprisingly found thatthe compounds of formula 1, 2, 3, 4, 5 or 6 as described and definedherein are potent inhibitors of mast cell degranulation and thusfunction as mast cell stabilizers and/or potent inhibitors of allergicand/or cellular inflammation. In particular, it was surprisingly foundthat the compounds as disclosed herein can be used therapeutically inthe treatment, prevention and/or amelioration of immunological disordersand disorders related to allergic and/or cellular inflammation, inparticular inflammatory, autoimmune and/or allergic disorders.

T helper (Th) cells are a subgroup of lymphocytes that play an importantrole in the immune system due to their participation in activating anddirecting other immune cells. The other major types of lymphocytes are Bcells and natural killer (NK) cells. During the antigenic activation andproliferation of Th cells, the Th0 cells differentiate into Th1, Th2 orother subtypes depending on the type of antigen, the antigen presentingcell and the cytokine environment.

Delayed type hypersensitivity, also called type IV hypersensitivity isan antibody-independent Th cell-mediated immune memory responseresulting from an over-stimulation of immune cells, commonly lymphocytesand macrophages, resulting in chronic inflammation and cytokine release.Important disease examples are contact dermatitis, chronic inflammationof ileum and colon, e.g. as seen in inflammatory bowel disease (IBD),rheumatoid arthritis and related diseases, ankylosing spondylitis,systemic lupus erythematosus, scleroderma, Gaucher's disease,fibromyalgia, osteoarthritis, reactive arthritis, pelvic inflammatorydisease, polymyalgia rheumatica, multiple sclerosis, Guillain-Barresyndrome, Hashimoto's thyroiditis, Grave's disease, and chronictransplant rejection. For IBD, for instance, Hue et al. demonstrated acausal relationship between the disease and T cell-mediated intestinalinflammation (Hue, S; et al. (2006) J. Exp. Med. 203 (11), 2473).

Psoriasis is a chronic autoimmune disease affecting the skin. Onehypothesis for the cause of psoriasis sees the disease as being animmune-mediated disorder in which the excessive reproduction of skincells is secondary to factors produced by the immune system. T cellsbecome active, migrate to the dermis and trigger the release ofcytokines which cause inflammation and the rapid production of skincells.

Mast cells, or mastocytes, play a key role in the inflammatory process.When activated, the mast cell rapidly releases its characteristicgranules and various hormonal mediators into the the interstitium, aprocess called degranulation. The molecules released into theextracellular environment include preformed mediators, e.g. histamineand serotonin, newly formed lipid mediators (eicosanoids) and cytokines.In allergic reactions, mast cells remain inactive until an allergenbinds to the IgE receptor expressed at the cell surface, leading todegranulation and release of mediators.

Many forms of cutaneous and mucosal allergies, in most cases accompaniedby inflammatory symptoms, are mediated largely by mast cells. They playa central role in asthma, eczema, itch and the various forms ofrhinitis, conjunctivitis and urticaria. Mast cells are also implicatedin the pathology associated with disorders such as rheumatoid arthritis,bullous pemphigoid and multiple sclerosis. They have been shown to beinvolved in the recruitment of inflammatory cells to the joints andskin. Moreover, mastocytosis is a disorder featuring proliferation ofmast cells and exists in a cutaneous and systemic form.

Atopic dermatitis, also known as neurodermitis, is an inflammatory andpruritic skin disorder characterised by chronic inflammation. Althoughthe causes underlying atopic dermatitis are not well understood and therelationships between intake of, or contact with, allergens and variousinflammatory stimuli are not well established, it is postulated thatmast cell and/or T cell-related processes are involved in thepathological processes leading to atopic dermatitis.

Asthma and chronic obstructive pulmonary disease (COPD) are bothobstructive airway disorders, but differing types of inflammation areinvolved in the pathogenesis of these diseases. Asthma is frequently anallergic process with a preponderance of Th2 cells and eosinophils inthe airways. In contrast, there is predominant Th1 activity in the bloodof COPD patients (Lecki, M J; et al. (2003) Thorax 58, 23).

Dry eye disease (DED) is an inflammatory disorder of the lacrimalfunctional unit leading to chronic ocular surface disease, impairedquality of vision, and a wide ranae of complications. It is recognizedthat a chronic inflammatory response plays a key role in thepathogenesis of human dry eye disease (Calonge M, et al. Ocul ImmunolInflamm. 2010. 18:244-253; Stevenson W, et al. Arch Ophthalmol. 2012.130:90-100; Zoukhri D. Exp Eye Res. 2006. 82:885-898; Pflugfelder S C.Am J Ophthalmol. 2004. 137:337-342).

Diabetic macular edema (or diabetic retinopathy) is characterized byearly retinal microvascular dysfunction and is a leading cause ofblindness in subjects suffering from diabetes. There is evidenceindicating that retinal inflammation plays an important role in thepathogenesis of diabetic macular edema (Joussen A M, et al. FASEBJ.2004. 18:1450-1452; Rangasamy S, et al. Middle East Afr J Ophthalmol.2012. 19:52-59; Meleth A D, et al. Invest Ophthalmol Vis Sci. 2005.46:4295-4301; Funatsu H, et al. Ophthalmology. 2009. 116:73-79; Kim S J,et al. Sury Ophthalmol. 2010. 55:108-133).

Accordingly, the compounds of the present invention, in particular thecompounds of formula 1, 2, 3, 4, 5 or 6, are useful in the treatment,prevention or amelioration of an inflammatory, autoimmune and/orallergic disorder.

The inflammatory, autoimmune and/or allergic disorder to be treated,prevented or ameliorated using the compounds of formula 1 or 2 accordingto the invention is selected from: psoriasis, atopic dermatitis (atopiceczema), contact dermatitis, xerotic eczema, seborrheic dermatitis,neurodermitis, dyshidrosis, discoid eczema, venous eczema, dermatitisherpetiformis (Duhring's Disease), autoeczematization, dermatomyositis,hyper-IgE (Buckley) syndrome, Wiskott-Aldrich syndrome, anaphylaxis,food allergy, or allergic reactions to venomous stings; acuteurticarias, chronic urticarias, physical urticarias including aquagenicurticaria, cholinergic urticaria, cold urticaria (chronic coldurticaria), delayed pressure urticaria, dermatographic urticaria, heaturticaria, solar urticaria, vibration urticaria, adrenergic urticaria,or urticaria angioedema; inflammatory bowel disease, Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, diversioncolitis (diverticulitis), Behçet's syndrome, indeterminate colitis,celiac disease, irritable bowel syndrome, post-operative ileus,eosinophilic gastroenteropathy, or gastritis; chronic allergic rhinitis,seasonal allergic rhinitis (hay-fever), allergic conjunctivitis,chemical conjunctivitis, neonatal conjunctivitis, Sjögren syndrome,open-angle glaucoma, dry eye disease (DED; including, e.g., aqueoustear-deficient dry eye (ADDE), Sjögren syndrome dry eye (SSDE),non-SSDE, or evaporative dry eye (EDE)), or diabetic macular edema (ordiabetic retinopathy); chronic obstructive pulmonary disease (COPD),allergic asthma, allergic bronchopulmonary aspergillosis,hypersensitivity pneumonitis, or lung fibrosis; rheumatoid arthritis,juvenile rheumatoid arthritis, ankylosing spondylitis, systemic lupuserythematosus (SLE), scleroderma, reactive arthritis, or polymyalgiarheumatica; Guillain-Barre syndrome, Hashimoto's thyroiditis, Grave'sdisease, temporal arteritis, primary biliary cirrhosis, sclerosingcholangitis, autoimmune hepatitis, or alopecia areata; or agraft-versus-host disease, a host-versus-graft disease or a transplantrejection.

Furthermore, the compounds of the present invention, in particular thecompounds of formula 1, 2, 3, 4, 5 or 6, have been demonstrated to beeffective in the inhibition of Akt kinase activation, as also shown inExample 7, and are thus useful in the treatment, prevention oramelioration of proliferative, neoplastic or dysplastic diseases ordisorders, which will be described in more detail in the following.

Evidence indicates that Akt plays a key role in cancer progression bystimulating cell proliferation and inhibiting apoptosis (Chen et al.,Cell Mol Immunol. 2:241-52 (2005)). Unregulated activation of thePI3K/Akt pathway commonly occurs in cancer through a variety ofmechanisms, including genetic mutations of kinases and regulatoryproteins, epigenetic alterations that alter gene expression andtranslation, and posttranslational modifications. Analysis of Akt levelsin human tumors showed that Akt is overexpressed in a significant numberof ovarian (Cheng et al., Proc Natl Acad Sci USA. 89:9267-9271(1992)),pancreatic (Cheng et al., Proc Natl Acad Sci USA. 93:3636-3641 (1996)),breast and prostate cancers (Nakatani et al., J Biol Chem.274:21528-21532 (1999)) and thyroid tumors (Saji and Ringel, Mol CellEndocrinol. 321:20-8 (2010). These observations demonstrate that thePI3K/Akt pathway plays important roles for regulating cell survival orapoptosis in tumorgenesis. Constitutive activation of the PI3K/Aktpathway promotes the long-term survival and outgrowth of cancer cells.The compounds of the present invention, which are inhibitors of Aktkinase activation, are thus envisaged to be used in the treatment,prevention or amelioration of a proliferative, neoplastic or dysplasticdisease or disorder, particularly cancer.

The compounds of the invention, which have been demonstrated to exhibitan efficacy in the suppression of the inflammatory response at leastequivalent to that of the corticosteroid dexamethasone, as also shown inExamples 8 and 9, are furthermore advantageous in that they do not showthe adverse effects observed for corticosteroids, such as reduction oflymph node weight and cell number which was observed for thecorticosteroid diflorasone in Example 9, which makes them particularlyuseful in the treatment, prevention or amelioration of inflammatory,autoimmune and/or allergic disorders.

Moreover, the compounds of the present invention, including thecompounds of formula 1, 2, 3, 4, 5 or 6, have a particularly lowcytotoxicity and, thus, an advantageous toxicity profile, as alsodemonstrated in Example 6.

The compound of formula 1 as defined above is described in more detailin the following.

R¹ is a C₁₀₋₂₀ hydrocarbon group. Preferably, R¹ is an alkyl group, analkenyl group, or an alkynyl group; more preferably. R¹ is a linearalkyl group, a linear alkenyl group, or a linear alkynyl group; evenmore preferably, R¹ is a linear alkyl group. The number of carbon atomsof the hydrocarbon group, the alkyl group, the alkenyl group, or thealkynyl group is 10 to 20, preferably 12, 14 or 16. Accordingly, it isparticularly preferred that R¹ is —(CH₂)₁₁—CH₃, —(CH₂)₁₃—CH₃, or—(CH₂)₁₅—CH₃.

R² is A C₁₋₄ alkyl group, and R³ is —H, a C₁₋₄ alkyl group or R³ isabsent; or

R² and R³ are mutually linked to form a pyrrolidine ring, a piperidinering or an azepane ring together with the nitrogen atom X to which theyare attached, wherein said pyrrolidine ring, said piperidine ring orsaid azepane ring is optionally substituted with one or more groupsindependently selected from —OH, —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂,—NH(C₁₋₃ alkyl) or —N(C₁₋₃ alkyl)(C₁₋₃ alkyl).

In one preferred embodiment, R² is methyl, and R³ is —H, a C₁₋₄ alkylgroup or R³ is absent. More preferably, R² is methyl, and R³ is —H,methyl or R³ is absent. Even more preferably. R² is methyl and R³ ismethyl.

In another preferred embodiment, R² and R³ are mutually linked to form apyrrolidine ring, a piperidine ring or an azepane ring together with thenitrogen atom X to which they are attached. More preferably, R² and R³are mutually linked to form a piperidine ring together with the nitrogenatom X to which they are attached. The pyrrolidine ring, the piperidinering or the azepane ring may be substituted with one or more (such as,e.g., one, two, three, or four), preferably one or two, more preferablyone, groups independently selected from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃alkyl)(C₁₋₃ alkyl). Preferably, the pyrrolidine ring, the piperidinering or the azepane ring is unsubstituted or substituted with one group—OH. Accordingly, it is particularly preferred that R² and R³ aremutually linked to form a piperidine ring together with the nitrogenatom X to which they are attached, wherein the piperidine ring isoptionally substituted with one group —OH, preferably in para positionwith respect to the nitrogen atom X.

R⁴ is a C₃₋₆ alkylene group, which is substituted with one or more (suchas, e.g., one, two, three, or four) groups, preferably one or twogroups, more preferably one group, independently selected from —OH,—O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl),—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(CH₂)₃OH. The alkylene group may be linear or branched;preferably, the alkylene group is linear. The alkylene group has 3 to 6(i.e., 3, 4, 5 or 6) carbon atoms, and preferably has 3 carbon atoms.The one or more groups with which the alkylene group is substitutedis/are preferably selected independently from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH.More preferably, the one or more groups with which the alkylene group issubstituted is/are selected independently from —OH, —O—C(O)—(C₁₋₃alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. It is particularly preferred that R⁴is —(CH₂)_(p)—CH(—R⁴¹)—CH₂—, wherein the moiety —(OH₂)_(p)— within thegroup —(CH₂)_(p)—CH(—R⁴¹)—CH₂— is connected to R⁵, p is an integer from1 to 4 (i.e., 1, 2, 3 or 4; preferably, p is 1), and R⁴¹ is selectedfrom —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl),—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(OH₂)₃OH, preferably from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH,and more preferably from —OH, —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or—O(CH₂)₃OH. Even more preferably, R⁴ is —CH₂—CH(—R⁴¹)—CH₂—, wherein R⁴¹is selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl),—O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl),—O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH, preferablyfrom —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or—O(CH₂)₃OH, and more preferably from —OH, —O—C(O)—(C₁₋₃ alkyl) or—O(CH₂)₂OH. Yet even more preferably, R⁴ is —CH₂—CH(—OH)—CH₂— or—CH₂—CH(—O—C(O)—(C₁₋₃ alkyl))—CH₂—.

R⁵ is —SO₃ ⁻, —SO₃H, —PO₃H⁻, —PO₃ ²⁻, —PO₃H₂, —PO₂(OC₁₋₃ alkyl)⁻,—PO₂H(OC₁₋₃ alkyl), —PO(OC₁₋₃ alkyl)₂, —CO₂ ⁻, —CO₂H, or —CO₂(C₁₋₃alkyl). Preferably, R⁵ is —SO₃ ⁻, —SO₃H, —PO₃H⁻, —PO₃ ²⁻, or —PO₃H₂. Inone preferred embodiment, R⁵ is —SO₃ ⁻ or —SO₃H. In another preferredembodiment, R⁵ is —PO₃ ²⁻, —PO₃H⁻, or —PO₃H₂.

X is N⁺ or, if R³ is absent, X is N.

A person skilled in the art understands that, if the compound of formula1 is provided in solution, the protonation of the acid group R⁵ dependson the pH of the solution. For example, if R⁵ is —PO₃H—, it may bepresent as —PO₃H₂ in a more acidic environment or as —PO₃ ²⁻in a morealkaline environment.

Likewise, a skilled person understands that, if the compound of formula1 is provided in solution and if R³ in formula 1 is —H or is absent, theprotonation of the nitrogen atom X and, accordingly, the charge at thenitrogen atom X depends on the pH of the solution. Thus, depending onthe pH of the solution, R³ may be —H and X may be N⁺, or R³ may beabsent and X may be N.

Preferred examples of the compound of formula 1 are the compounds 1a,1b, 1c, 1d or 1e shown below or pharmaceutically acceptable salts,solvates or prodrugs thereof:

In one embodiment described above, R² and R³ in formula 1 are mutuallylinked to form a pyrrolidine ring, a piperidine ring or an azepane ringtogether with the nitrogen atom X to which they are attached, whereinsaid pyrrolidine ring, said piperidine ring or said azepane ring isoptionally substituted with one or more groups independently selectedfrom —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂,—NH(C₁₋₃ alkyl) or —N(C₁₋₃ alkyl)(C₁₋₃ alkyl).

Accordingly, the compound of formula 1 may be a compound of thefollowing formula 2

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

In formula 2, the groups R¹, R⁴, and R⁵ have the meanings or thepreferred meanings defined herein above for the compound of formula 1.

n is 1, 2, or 3. Preferably, n is 2.

m is an integer from 0 to 4. Preferably, m is 0, 1, or 2; morepreferably, m is 0 or 1; even more preferably, m is 1.

Each R⁶ is independently selected from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃alkyl)(C₁₋₃ alkyl). Preferably, each R⁶ is —OH.

It is to be understood that each R⁶ is attached to a carbon atom of thepyrrolidine, piperidine or azepane ring. It is further to be understoodthat, if m is 0, the pyrrolidine, piperidine or azepane ring (to whichR⁶ would be attached) is unsubstituted, i.e. is substituted withhydrogen.

In one embodiment, n is 1 or 3, and m is 0.

In a preferred embodiment, n is 2, m is 1, and R⁶ is —OH, —O(C₁₋₃alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), in particular —OH. In this embodiment, it isfurther preferred that R⁶ is in para position in respect of the ringnitrogen atom N.

The invention furthermore relates to a compound of formula 3 or apharmaceutically acceptable salt, solvate or prodrug thereof for use asa medicament.

In formula 3, the groups R¹, R², R³, R⁵, and X have the same meaningsand preferred meanings as described and defined herein above for thecorresponding groups in formula 1.

Accordingly, R² in formula 3 is a C₁₋₄ alkyl group, and R³ is —H, a C₁₋₄alkyl group or R³ is absent; or R² and R³ are mutually linked to form apyrrolidine ring, a piperidine ring or an azepane ring together with thenitrogen atom X to which they are attached, wherein said pyrrolidinering, said piperidine ring or said azepane ring is optionallysubstituted with one or more groups independently selected from —OH,—O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl)or —N(C₁₋₃ alkyl)(C₁₋₃ alkyl).

If R² and R³ are not mutually linked, then R⁴ in formula 3 is—CH₂—CH(—OH)—CH₂— or R⁴ is a C₃₋₆ alkylene group which is substitutedwith one or more groups independently selected from —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂,—O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or—O(CH₂)₃OH. If R² and R³ are mutually linked to form a pyrrolidine ring,a piperidine ring or an azepane ring together with the nitrogen atom Xto which they are attached, then R⁴ in formula 3 is a C₃₋₆ alkylenegroup which is substituted with one or more groups independentlyselected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH.

Accordingly, if R² and R³ are not mutually linked, R⁴ in formula 3 is—CH₂—CH(—OH)—CH₂— or R⁴ is a C₃₋₆ alkylene group, wherein said C₃₋₆alkylene group is substituted with one or more (such as, e.g., one, two,three, or four) groups, preferably one or two groups, more preferablyone group, independently selected from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl),—O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. Thealkylene group may be linear or branched; preferably, the alkylene groupis linear. The alkylene group has 3 to 6 (i.e., 3, 4, 5 or 6) carbonatoms, and preferably has 3 carbon atoms. The one or more groups withwhich the alkylene group is substituted is/are preferably selectedindependently from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃alkyl), —O(OH₂)₂OH, or —O(CH₂)₃OH. More preferably, the one or moregroups with which the alkylene group is substituted is/are selectedindependently from —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. Itis particularly preferred that R⁴ is —CH₂—CH(—OH)—CH₂— or—(CH₂)_(p)—CH(—R⁴¹)—CH₂—, wherein the moiety —(CH₂)_(p)— within thegroup —(CH₂)_(p)—CH(—R⁴¹)—CH₂— is connected to R⁵, p is an integer from1 to 4 (i.e., 1, 2, 3 or 4; preferably, p is 1), and R⁴¹ is selectedfrom —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl),—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(CH₂)₃OH, preferably from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH, and morepreferably from —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. Evenmore preferably, R⁴ is —OH₂—CH(—R⁴¹)—CH₂—, wherein R⁴¹ is selected from—OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl),—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(CH₂)₃OH, preferably from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH, and more preferablyfrom —OH, —O—C(O)—(C₁₋₃ alkyl) or —O(CH₂)₂OH. Yet even more preferably,R⁴ is —CH₂—CH(—OH)—OH₂— or —CH₂—CH(—O—C(O)—(C₁₋₃ alkyl))—OH₂—.

If R² and R³ are mutually linked to form a pyrrolidine ring, apiperidine ring or an azepane ring together with the nitrogen atom X towhich they are attached, then R⁴ in formula 3 is a C₃₋₆ alkylene group,which is substituted with one or more (such as, e.g., one, two, three,or four) groups, preferably one or two groups, more preferably onegroup, independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl),—O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. Thealkylene group may be linear or branched; preferably, the alkylene groupis linear. The alkylene group has 3 to 6 (i.e., 3, 4, 5 or 6) carbonatoms, and preferably has 3 carbon atoms. The one or more groups withwhich the alkylene group is substituted is/are preferably selectedindependently from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl),—O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. More preferably, theone or more groups with which the alkylene group is substituted is/areselected independently from —OH, —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or—O(CH₂)₃OH. It is particularly preferred that R⁴ is—(OH₂)_(p)—CH(—R⁴¹)—CH₂—, wherein the moiety —(CH₂)_(p)— within thegroup —(CH₂)_(p)—CH(—R⁴¹)—CH₂— is connected to R⁵, p is an integer from1 to 4 (i.e., 1, 2, 3 or 4; preferably, p is 1), and R⁴¹ is selectedfrom —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl),—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(CH₂)₃OH, preferably from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH,and more preferably from —OH, —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or—O(CH₂)₃OH. Even more preferably, R⁴ is —CH₂—CH(—R⁴¹)—CH₂—, wherein R⁴¹is selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl),—O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl),—O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH, preferablyfrom —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or—O(CH₂)₃OH, and more preferably from —OH, —O—C(O)—(C₁₋₃ alkyl) or—O(CH₂)₂OH. Yet even more preferably, R⁴ is —CH₂—CH(—OH)—CH₂— or—CH₂—CH(—O—C(O)—(C₁₋₃ alkyl))—OH₂—.

Preferred examples of the compound of formula 3 are the compounds 1a,1b, 1c, 1d or 1e shown below or pharmaceutically acceptable salts,solvates or prodrugs thereof:

In accordance with the above definition of the compound of formula 3,the groups R² and R³ may, in one embodiment, be mutually linked to forma pyrrolidine ring, a piperidine ring or an azepane ring together withthe nitrogen atom X to which they are attached, wherein said pyrrolidinering, said piperidine ring or said azepane ring is optionallysubstituted with one or more groups independently selected from —OH,—O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl)or —N(C₁₋₃ alkyl)(C₁₋₃ alkyl).

The compound of formula 3, which is provided herein as a medicament, maythus be a compound of the following formula 4

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The groups R¹ and R⁵ in formula 4 have the same meanings and preferredmeanings as defined herein above for the corresponding groups in formula3.

In formula 4, n is 1, 2, or 3. Preferably, n is 2.

m is an integer from 0 to 4. Preferably, m is 0, 1, or 2; morepreferably, m is 0 or 1; even more preferably, m is 1.R⁴ in formula 4 is a C₃₋₆ alkylene group which is substituted with oneor more (such as, e.g., one, two, three, or four) groups, preferably oneor two groups, more preferably one group, independently selected from—OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl),—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(CH₂)₃OH. The alkylene group may be linear or branched;preferably, the alkylene group is linear. The alkylene group has 3 to 6(i.e., 3, 4, 5 or 6) carbon atoms, and preferably has 3 carbon atoms.The one or more groups with which the alkylene group is substitutedis/are preferably selected independently from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH.More preferably, the one or more groups with which the alkylene group issubstituted is/are selected independently from —OH, —O—C(O)—(C₁₋₃alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. It is particularly preferred that R⁴is —(CH₂)_(p)—CH(—R⁴¹)—CH₂—, wherein the moiety —(CH₂)_(p)— within thegroup —(CH₂)_(p)—CH(—R⁴¹)—CH₂— is connected to R⁵, p is an integer from1 to 4 (i.e., 1, 2, 3 or 4; preferably, p is 1), and R⁴¹ is selectedfrom —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl),—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(OH₂)₃OH, preferably from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH,and more preferably from —OH, —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or—O(CH₂)₃OH. Even more preferably, R⁴ is —CH₂—CH(—R⁴¹)—CH₂—, wherein R⁴¹is selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl),—O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl),—O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH, preferablyfrom —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or—O(CH₂)₃OH, and more preferably from —OH, —O—C(O)—(C₁₋₃ alkyl) or—O(CH₂)₂OH. Yet even more preferably, R⁴ is —CH₂—CH(—OH)—CH₂— or—CH₂—CH(—O—C(O)—(C₁₋₃ alkyl))—CH₂—.

Each R⁶ in formula 4 is independently selected from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃alkyl)(C₁₋₃ alkyl). Preferably, each R⁶ is —OH.

It is to be understood that each R⁶ is attached to a carbon atom of thepyrrolidine, piperidine or azepane ring. It is further to be understoodthat, if m is 0, the pyrrolidine, piperidine or azepane ring (to whichR⁶ would be attached) is unsubstituted, i.e. is substituted withhydrogen.

In one embodiment, n is 1 or 3, and m is 0.

In a preferred embodiment, n is 2, m is 1, and R⁶ is —OH, —O(C₁₋₃alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), in particular —OH. In this embodiment, it isfurther preferred that R⁶ is in para position in respect of the ringnitrogen atom N⁺.

The present invention also relates to a pharmaceutical compositioncomprising a compound of formula 3 or 4, as described and definedherein, or a pharmaceutically acceptable salt, solvate or prodrugthereof, and a pharmaceutically acceptable excipient.

The invention further relates to a compound of formula 3 or 4, asdescribed and defined herein, or a pharmaceutically acceptable salt,solvate or prodrug thereof, or a pharmaceutical composition comprisingany of the aforementioned entities and a pharmaceutically acceptableexcipient, for use in the treatment, prevention or amelioration of aninflammatory, autoimmune and/or allergic disorder.

Moreover, the present invention relates to a method of treating,preventing or ameliorating a disease or disorder, in particular aninflammatory, autoimmune and/or allergic disorder, the method comprisingthe administration of a compound of formula 3 or 4, as described anddefined herein, or a pharmaceutically acceptable salt, solvate orprodrug thereof, or a pharmaceutical composition comprising any of theaforementioned entities and a pharmaceutically acceptable excipient, toa subject (preferably, a human or a non-human mammal) in need of such atreatment, prevention or amelioration.

The inflammatory, autoimmune and/or allergic disorder to be treated,prevented or ameliorated using the compounds of formula 3 or 4 accordingto the invention is, for example, selected from: psoriasis, atopicdermatitis (atopic eczema), contact dermatitis, xerotic eczema,seborrheic dermatitis, neurodermitis, dyshidrosis, discoid eczema,venous eczema, dermatitis herpetiformis (Duhring's Disease),autoeczematization, dermatomyositis, hyper-IgE (Buckley) syndrome,Wiskott-Aldrich syndrome, anaphylaxis, food allergy, or allergicreactions to venomous stings; acute urticarias, chronic urticarias,physical urticarias including aquagenic urticaria, cholinergicurticaria, cold urticaria (chronic cold urticaria), delayed pressureurticaria, dermatographic urticaria, heat urticaria, solar urticaria,vibration urticaria, adrenergic urticaria, or urticaria angioedema;inflammatory bowel disease, Crohn's disease, ulcerative colitis,collagenous colitis, lymphocytic colitis, diversion colitis(diverticulitis), Behçet's syndrome, indeterminate colitis, celiacdisease, irritable bowel syndrome, post-operative ileus, eosinophilicgastroenteropathy, or gastritis; chronic allergic rhinitis, seasonalallergic rhinitis (hay-fever), allergic conjunctivitis, chemicalconjunctivitis, neonatal conjunctivitis, Sjögren syndrome, open-angleglaucoma, dry eye disease (DED; including, e.g., aqueous tear-deficientdry eye (ADDE), Sjögren syndrome dry eye (SSDE), non-SSDE, orevaporative dry eye (EDE)), or diabetic macular edema (or diabeticretinopathy); chronic obstructive pulmonary disease (COPD), allergicasthma, allergic bronchopulmonary aspergillosis, hypersensitivitypneumonitis, or lung fibrosis; rheumatoid arthritis, juvenile rheumatoidarthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE),scleroderma, osteoarthritis, reactive arthritis, or polymyalgiarheumatica; multiple sclerosis, Guillain-Barre syndrome, Hashimoto'sthyroiditis, Grave's disease, temporal arteritis, primary biliarycirrhosis, sclerosing cholangitis, autoimmune hepatitis, alopecia areataor autoimmune lymphoproliferative syndrome (ALPS); a graft-versus-hostdisease, a host-versus-graft disease or a transplant rejection; or aninflammatory contribution to Alzheimer's disease or Parkinson's disease.

Furthermore, the invention relates to a compound of formula 3 or 4 or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising any of the aforementioned entitiesand a pharmaceutically acceptable excipient, for use in the treatment,prevention or amelioration of a proliferative, neoplastic or dysplasticdisease or disorder. The invention also encompasses a method oftreating, preventing or ameliorating a proliferative, neoplastic ordysplastic disease or disorder, the method comprising the administrationof a compound of formula 3 or 4 or a pharmaceutically acceptable salt,solvate or prodrug thereof, or a pharmaceutical composition comprisingany of the aforementioned entities and a pharmaceutically acceptableexcipient, to a subject (preferably, a human or a non-human mammal) inneed of such a treatment, prevention or amelioration.

The proliferative, neoplastic or dysplastic disease or disorder to betreated, prevented or ameliorated using a compound of formula 3 or 4according to the invention is, for example, a benign or malignantneoplasia, such as, e.g., leukemia, adrenocortical carcinoma, anAIDS-related cancer, appendix cancer, astrocytoma, basal cell carcinoma,bile duct cancer, bladder cancer, bone cancer, brain tumor, breastcancer, a bronchial adenoma, Burkitt lymphoma, carcinoid tumor, centralnervous system lymphoma, cerebellar astrocytoma, cervical cancer, coloncancer, cutaneous T-cell lymphoma, chronic lymphovytic leukemia, chronicmyelogenous leukemia, a chronic myeloproliferative disorder,desmoplastic small round cell tumor, endometrial cancer, ependymoma,esophageal cancer, Ewing's sarcoma, extracranial germ cell tumor,extrahepatic bile duct cancer, intraocular melanoma, retinoblastoma,gallbladder cancer, gastric cancer, gastric carcinoid, gastrointestinalcarcinoid tumor, gastrointestinal stromal tumor, germ cell tumor,glioma, gestational trophoblastic tumor, head and neck cancer, heartcancer, hepatocellular cancer, Hodgkin lymphoma, Non-Hodgkin lymphoma,hypopharyngeal cancer, hypthalamic and visual pathway glioma,intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, renal cellcancer, laryngeal cancer, lip and oral cavity cancer, lung cancer,Waldenstrom's macroglobulinemia, osteosarcoma, medulloblastoma,melanoma, Merkel cell carcinoma, mesothelioma, mouth cancer, multipleendocrine neoplasia syndrome, plasma cell neoplasm, mycosis fungoides, amyelodysplastic disease, multiple myeloma, a myeloproliferativedisorder, nasal cavity and paranasal sinus cancer, nasopharyngealcarcinoma, neuroblastoma, oral cancer, oropharyngeal cancer, ovariancancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatictumor, parathyroid cancer, penile cancer, pharyngeal cancer,pheochromocytoma, pineal astrocytoma, pineal germinoma, pineoblastoma,pituitary adenoma, pleuropulmonary blastoma, prostate cancer, rectalcancer, transitional cell cancer, rhabdomyosarcoma, salivary glandcancer, Szary syndrome, skin cancer, small cell lung cancer, smallintestine cancer, soft tissue sarcoma, stomach cancer, supratentorialprimitive neuroectodermal tumor, testicular cancer, throat cancer,thymoma, thyroid cancer, uterine cancer, uterine sarcoma, vaginalcancer, vulvar cancer, or Wilms tumor.

The invention furthermore provides novel compounds. These compounds aredescribed herein and are characterized by formula 5

or pharmaceutically acceptable salts, solvates or prodrugs thereof.These compounds as provided in the context of the present invention areparticularly useful as pharmaceuticals.

In formula 5, the groups R¹, R⁵ and X have the same meanings andpreferred meanings as described and defined herein above for thecorresponding groups in formula 1, while the groups R², R³ and R⁴ informula 5 have the following meanings:

Either (i) R² is a C₁₋₄ alkyl group, R³ is —H or is absent, and R⁴ is—CH₂—CH(—OH)—CH₂—;

or (ii) R² is a C₁₋₄ alkyl group, R³ is —H, a C₁₋₄ alkyl group or isabsent, and R⁴ is a C₃₋₆ alkylene group which is substituted with one ormore groups independently selected from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl),—O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH;or (iii) R² and R³ are mutually linked to form a pyrrolidine ring, apiperidine ring or an azepane ring together with the nitrogen atom X towhich they are attached, wherein said pyrrolidine ring, said piperidinering or said azepane ring is optionally substituted with one or moregroups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃ alkyl)(C₁₋₃ alkyl),and R⁴ is a C₃₋₆ alkylene group which is substituted with one or moregroups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl),—O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH.

In one preferred embodiment, R² in formula 5 is methyl, R³ is —H or isabsent, and R⁴ is —CH₂—CH(—OH)—CH₂—.

In another further preferred embodiment, R² in formula 5 is methyl, R³is —H, a C₁₋₄ alkyl group (particularly methyl) or is absent, and R⁴ isa C₃₋₆ alkylene group which is substituted with one or more groupsindependently selected from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl),—O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl),—O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH. Said C₃₋₆alkylene group may be linear or branched; preferably, the alkylene groupis linear. The alkylene group has 3 to 6 (i.e., 3, 4, 5 or 6) carbonatoms, and preferably has 3 carbon atoms. The one or more groups withwhich the alkylene group is substituted is/are preferably selectedindependently from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. More preferably, the one or moregroups with which the alkylene group is substituted is/are selectedindependently from —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. Morepreferably, R² is methyl, R³ is —H, methyl or is absent, and R⁴ is—(CH₂)_(p)—CH(—R⁴¹)—CH₂—, wherein the moiety —(CH₂)_(p)— within thegroup —(CH₂)_(p)—CH(—R⁴¹)—CH₂— is connected to R⁵, p is an integer from1 to 4 (i.e., 1, 2, 3 or 4; preferably, p is 1), and R⁴¹ is selectedfrom —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl),—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(CH₂)₃OH, preferably from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH, and morepreferably from —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. Evenmore preferably, R² is methyl, R³ is —H, methyl or is absent, and R⁴ is—CH₂—CH(—R⁴¹)—CH₂—, wherein R⁴¹ is selected from —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂,—O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH,or —O(CH₂)₃OH, preferably from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(CH₂)₃OH, and more preferably from —O—C(O)—(C₁₋₃ alkyl)or —O(CH₂)₂OH. Yet even more preferably, R² is methyl, R³ is —H, methylor is absent, and R⁴ is —CH₂—CH(—O—C(O)—(C₁₋₃ alkyl))—CH₂—. In theaforementioned embodiments of R², R³ and R⁴, it is particularlypreferred that R³ is methyl.

In another preferred embodiment, R² and R³ in formula 5 are mutuallylinked to form a pyrrolidine ring, a piperidine ring or an azepane ring(preferably a piperidine ring) together with the nitrogen atom X towhich they are attached, wherein the pyrrolidine ring, the piperidinering or the azepane ring may be substituted with one or more (such as,e.g., one, two, three, or four), preferably one or two, more preferablyone, groups independently selected from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃alkyl)(C₁₋₃ alkyl); and R⁴ is a C₃₋₆ alkylene group which is substitutedwith one or more (such as, e.g., one, two, three, or four) groups,preferably one or two groups, more preferably one group, independentlyselected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. Said C₃₋₆ alkylene group (R⁴) may belinear or branched and preferably is linear. The alkylene group has 3 to6 (i.e., 3, 4, 5 or 6) carbon atoms, and preferably has 3 carbon atoms.The one or more groups with which the alkylene group (R⁴) is substitutedis/are preferably selected independently from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH.More preferably, the one or more groups with which the alkylene group(R⁴) is substituted is/are selected independently from —OH,—O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. It is furthermorepreferred that said pyrrolidine ring, said piperidine ring or saidazepane ring (R² and R³) is unsubstituted or substituted with one group—OH. Accordingly, it is particularly preferred that R² and R³ aremutually linked to form a piperidine ring together with the nitrogenatom X to which they are attached, wherein the piperidine ring isoptionally substituted with one group —OH, preferably in para positionwith respect to the nitrogen atom X, and R⁴ is —(CH₂)_(p)—CH(—R⁴¹)—CH₂—,wherein the moiety —(CH₂)_(p)— within the group —(OH₂)_(p)—CH(—R⁴¹)—CH₂—is connected to R⁵, p is an integer from 1 to 4 (i.e., 1, 2, 3 or 4;preferably, p is 1), and R⁴¹ is selected from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂,—O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH,or —O(CH₂)₃OH, preferably from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH, and morepreferably from —OH, —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH.More preferably, R² and R³ are mutually linked to form a piperidine ringtogether with the nitrogen atom X to which they are attached, whereinthe piperidine ring is optionally substituted with one group —OH(preferably in para position with respect to the nitrogen atom X), andR⁴ is —CH₂—CH(—R⁴¹)—CH₂—, wherein R⁴¹ is selected from —OH, —O(C₁₋₃alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂,—O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH,or —O(CH₂)₃OH, preferably from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH, and more preferably from —OH,—O—C(O)—(C₁₋₃ alkyl) or —O(CH₂)₂OH. Even more preferably, R² and R³ aremutually linked to form a piperidine ring together with the nitrogenatom X to which they are attached, wherein the piperidine ring isoptionally substituted with one group —OH (preferably in para positionwith respect to the nitrogen atom X), and R⁴ is —CH₂—CH(—OH)—CH₂— or—CH₂—CH(—O—C(O)—(C₁₋₃ alkyl))—CH₂—.

Preferred examples of the compound of formula 5 are the compounds 1a,1b, 1c, 1d or 1e shown below or pharmaceutically acceptable salts,solvates or prodrugs thereof:

The compound of formula 5 may, in accordance with the above definition,also be a compound of the following formula 6

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

The groups R¹ and R⁵ in formula 6 have the same meanings and preferredmeanings as defined herein above for the corresponding groups in formula5.

In formula 6, n is 1, 2, or 3. Preferably, n is 2.

m is an integer from 0 to 4. Preferably, m is 0, 1, or 2; morepreferably, m is 0 or 1; even more preferably, m is 1.

R⁴ in formula 6 is a C₃₋₆ alkylene group which is substituted with oneor more (such as, e.g., one, two, three, or four) groups, preferably oneor two groups, more preferably one group, independently selected from—OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl),—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(CH₂)₃OH. The alkylene group may be linear or branched;preferably, the alkylene group is linear. The alkylene group has 3 to 6(i.e., 3, 4, 5 or 6) carbon atoms, and preferably has 3 carbon atoms.The one or more groups with which the alkylene group is substitutedis/are preferably selected independently from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH.More preferably, the one or more groups with which the alkylene group issubstituted is/are selected independently from —OH, —O—C(O)—(C₁₋₃alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH. It is particularly preferred that R⁴is —(CH₂)_(p)—CH(—R⁴¹)—CH₂—, wherein the moiety —(CH₂)_(p)— within thegroup —(CH₂)_(p)—CH(—R⁴¹)—CH₂— is connected to R⁵, p is an integer from1 to 4 (i.e., 1, 2, 3 or 4; preferably, p is 1), and R⁴¹ is selectedfrom —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl),—O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl),—O(CH₂)₂OH, or —O(CH₂)₃OH, preferably from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH,and more preferably from —OH, —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or—O(CH₂)₃OH. Even more preferably, R⁴ is —CH₂—CH(—R⁴¹)—CH₂—, wherein R⁴¹is selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl),—O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl),—O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH, preferablyfrom —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O(CH₂)₂OH, or—O(CH₂)₃OH, and more preferably from —OH, —O—C(O)—(C₁₋₃ alkyl) or—O(CH₂)₂OH. Yet even more preferably, R⁴ is —CH₂—OH(—OH)—CH₂— or—CH₂—CH(—O—C(O)—(C₁₋₃ alkyl))—CH₂—.

Each R⁶ in formula 6 is independently selected from —OH, —O(C₁₋₃ alkyl),—O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃alkyl)(C₁₋₃ alkyl). Preferably, each R⁶ is —OH.

It is to be understood that each R⁶ is attached to a carbon atom of thepyrrolidine, piperidine or azepane ring. It is further to be understoodthat, if m is 0, the pyrrolidine, piperidine or azepane ring (to whichR⁶ would be attached) is unsubstituted, i.e. is substituted withhydrogen.

In one embodiment, n is 1 or 3, and m is 0.

In a preferred embodiment, n is 2, m is 1, and R⁶ is —OH, —O(C₁₋₃alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), in particular —OH. In this embodiment, it isfurther preferred that R⁶ is in para position in respect of the ringnitrogen atom N⁺.

In accordance with the disclosure of the present invention, thecompounds of formulae 5 and 6 can be used as medicaments, particularlyin the treatment, prevention or amelioration of an inflammatory,autoimmune and/or allergic disorder and also in the treatment,prevention or amelioration of a proliferative, neoplastic or dysplasticdisease or disorder, including the specific disorders described anddiscussed herein above in connection with the compounds of formulae 3and 4.

The compounds to be used in accordance with the present invention, inparticular the compounds of formula 1, 2, 3, 4, 5 or 6, can be preparedby methods known in the field of synthetic chemistry.

For example, compounds of the general formula 1, 3 or 5 can be preparedby N-alkylation of N-alkylated alkylamines (or other N-alkylatedhydrocarbylamines, such as, e.g., N-alkylated alkenylamines orN-alkylated alkynylamines) using appropriately hydroxysubstitutedω-chloro-1-alkanesulfonates under basic conditions. In a similar way,the related phosphonates or carboxylates are generated, e.g., by usingappropriately hydroxysubstituted ω-chloro-1-alkanephosphonates orappropriately hydroxysubstituted w-chloro-1-alkanecarboxylates. Thecorresponding N,N-dialkylated quarternary ammonium derivatives can beobtained by standard N-alkylation using, e.g., alkyl iodides.

Compounds of the general formula 2, 4 or 6 can be prepared byconsecutive N-alkylation of appropriately functionalised pyrrolidine,piperidine or azepane derivatives using the aforementioned appropriatelyhydroxysubstituted w-chloro-1-alkanesulfonates, -phosphonates or-carboxylates followed by alkyl iodides.

In addition to the unsubstituted hydroxyl derivatives of general formula1 or 2 (i.e., compounds of formula 1 or 2 in which R⁴ is an alkylenesubstituted with —OH), subsequent O-alkylation, O-acylation orO-carbamoylation using protocols employed in the literature provide thecorresponding O-functionalised derivatives.

The compounds of formula 1, 2, 3, 4, 5 or 6 can also be prepared inanalogy to the synthetic routes described in the examples section.

As used herein, the term “hydrocarbon group” refers to a groupconsisting of carbon atoms and hydrogen atoms, which group may besaturated or unsaturated, linear, branched or cyclic, aliphatic oraromatic. A “C₁₀₋₂₀ hydrocarbon group” denotes a hydrocarbon grouphaving 10 to 20 carbon atoms.

As used herein, the term “alkyl group” refers to a monovalent saturatedaliphatic (i.e. non-aromatic) acyclic hydrocarbon group, which may belinear or branched and does not comprise any carbon-to-carbon doublebond or any carbon-to-carbon triple bond.

As used herein, the term “alkenyl group” refers to a monovalentunsaturated aliphatic acyclic hydrocarbon group, which may be linear orbranched and comprises at least one carbon-to-carbon double bond whileit does not comprise any carbon-to-carbon triple bond.

As used herein, the term “alkynyl group” refers to a monovalentunsaturated aliphatic acyclic hydrocarbon group, which may be linear orbranched and comprises at least one carbon-to-carbon triple bond andoptionally one or more carbon-to-carbon double bonds.

As used herein, the term “alkylene group” refers to a divalent saturatedaliphatic (i.e. non-aromatic) acyclic hydrocarbon group which may belinear or branched and does not comprise any carbon-to-carbon doublebond or any carbon-to-carbon triple bond.

The scope of the invention embraces all pharmaceutically acceptable saltforms of the compounds of formula 1, 2, 3, 4, 5 or 6, which may beformed, e.g., by protonation of an atom carrying an electron lone pairwhich is susceptible to protonation, such as an amino group, with aninorganic or organic acid, or as a salt of a carboxylic acid group witha physiologically acceptable cation as they are well-known in the art.Exemplary base addition salts comprise, for example, alkali metal saltssuch as sodium or potassium salts; alkaline earth metal salts, such ascalcium or magnesium salts; ammonium salts; aliphatic amine salts, suchas trimethylamine, triethylamine, dicyclohexylamine, ethanolamine,diethanolamine, triethanolamine, procaine salts, meglumine salts,diethanol amine salts or ethylenediamine salts; aralkyl amine salts suchas N,N-dibenzylethylenediamine salts, benetamine salts; heterocyclicaromatic amine salts, such as pyridine salts, picoline salts, quinolinesalts or isoquinoline salts; quaternary ammonium salts, such astetramethylammonium salts, tetraethylammonium salts,benzyltrimethylammonium salts, benzyltriethylammonium salts,benzyltributylammonium salts, methyltrioctylammonium salts ortetrabutylammonium salts; and basic amino acid salts, such as argininesalts or lysine salts. Exemplary acid addition salts comprise, forexample, mineral acid salts, such as hydrochloride, hydrobromide,hydroiodide, sulfate salts, nitrate salts, phosphate salts (such asphosphate, hydrogenphosphate or dihydrogenphosphate salts), carbonatesalts, hydrogencarbonate salts or perchlorate salts; organic acid saltssuch as acetate, propionate, butyrate, pentanoate, hexanoate,heptanoate, octanoate, cyclopentanepropionate, undecanoate, lactate,maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate,benzoate, salicylate or ascorbate salts; sulfonate salts, such asmethanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate,benzenesulfonate, p-toluenesulfonate (tosylate), 2-naphthalenesulfonate,3-phenylsulfonate, or camphorsulfonate salts; and acidic amino acidsalts, such as aspartate or glutamate salts.

Moreover, the scope of the invention embraces solid forms of thecompounds of formula 1, 2, 3, 4, 5 or 6 in any solvated form, includinge.g. solvates with water, for example hydrates, or with organicsolvents, such as, e.g., methanol, ethanol, isopropanol or acetonitrile,i.e. as a methanolate, ethanolate, isopropanolate or acetonitrilate,respectively; or in the form of any polymorph. The invention alsoembraces each one of the polymorphs of compound 1a described in Example5.

Furthermore, the formulae in the present application are intended tocover all possible stereoisomers, including enantiomers anddiastereomers, of the indicated compounds.

Thus, all stereoisomers of the compounds of the present invention, inparticular the compounds of formula 1, 2, 3, 4, 5 or 6, are contemplatedas part of the present invention, either in admixture or in pure orsubstantially pure form. The scope of the compounds according to theinvention embraces all the possible stereoisomers and their mixtures. Itvery particularly embraces the racemic forms and the isolated opticalisomers. The racemic forms can be resolved by physical methods, such as,e.g., fractional crystallization, separation or crystallization ofdiastereomeric derivatives or separation by chiral columnchromatography. The individual optical isomers can be obtained from theracemates using conventional methods, such as, e.g., salt formation withan optically active acid followed by crystallization.

Pharmaceutically acceptable prodrugs of compounds of the presentinvention, in particular of the compounds of formula 1, 2, 3, 4, 5 or 6,are derivatives which have chemically or metabolically cleavable groupsand become, by solvolysis or under physiological conditions, thecompounds of the present invention which are pharmaceutically active invivo. Prodrugs of compounds of the present invention may be formed in aconventional manner with a functional group of the compounds, such aswith an amino, hydroxy or carboxy group. The prodrug derivative formoften offers advantages of solubility, tissue compatibility or delayedrelease in a mammalian organism (see, Bundgaard, H., Design of Prodrugs,pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acidderivatives well known to the person skilled in the art, such as, forexample, esters prepared by reaction of the parent acidic compound witha suitable alcohol, or amides prepared by reaction of the parent acidcompound with a suitable amine. When a compound of the present inventionhas a carboxyl group, an ester derivative prepared by reacting thecarboxyl group with a suitable alcohol or an amide derivative preparedby reacting the carboxyl group with a suitable amine is exemplified as aprodrug. An especially preferred ester derivative as a prodrug ismethylester, ethylester, n-propylester, isopropylester, n-butylester,isobutylester, tert-butylester, morpholinoethylester,N,N-diethylglycolamidoester or α-acetoxyethylester. When a compound ofthe present invention has a hydroxy group, an acyloxy derivativeprepared by reacting the hydroxyl group with a suitable acylhalide or asuitable acid anhydride is exemplified as a prodrug. An especiallypreferred acyloxy derivative as a prodrug is —OC(═O)—CH₃, —OC(═O)—C₂H₅,—OC(═O)-(tert-Bu), —OC(═O)—C₁₅H₃₁, —OC(═O)-(m-COONa—Ph),—OC(═O)—CH₂CH₂COONa, —O(C═O)—CH(NH₂)CH₃ or —OC(═O)—CH₂—N(CH₃)₂. When acompound of the present invention has an amino group, an amidederivative prepared by reacting the amino group with a suitable acidhalide or a suitable mixed anhydride is exemplified as a prodrug. Anespecially preferred amide derivative as a prodrug is—NHC(═O)—(CH₂)₂OCH₃ or —NHC(═O)—CH(NH₂)CH₃.

The compounds described herein may be administered as compounds per sein their use as pharmacophores or pharmaceutical compositions or may beformulated as medicaments. Within the scope of the present invention arepharmaceutical compositions comprising, as an active ingredient, acompound of formula 1, 2, 3, 4, 5 or 6 as defined above. Thepharmaceutical compositions may optionally comprise one or morepharmaceutically acceptable excipients, such as carriers, diluents,fillers, disintegrants, lubricating agents, binders, colorants,pigments, stabilizers, preservatives, or antioxidants.

The pharmaceutical compositions can be formulated by techniques known tothe person skilled in the art, such as the techniques published inRemington's Pharmaceutical Sciences, 20^(th) Edition. The pharmaceuticalcompositions can be formulated as dosage forms for oral, parenteral,such as intramuscular, intravenous, subcutaneous, intradermal,intraarterial, rectal, nasal, topical, aerosol or vaginaladministration. Dosage forms for oral administration include coated anduncoated tablets, soft gelatin capsules, hard gelatin capsules,lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs,powders and granules for reconstitution, dispersible powders andgranules, medicated gums, chewing tablets and effervescent tablets.Dosage forms for parenteral administration include solutions, emulsions,suspensions, dispersions and powders and granules for reconstitution.Emulsions are a preferred dosage form for parenteral administration.Dosage forms for rectal and vaginal administration include suppositoriesand ovula. Dosage forms for nasal administration can be administered viainhalation and insufflation, for example by a metered inhaler. Dosageforms for topical administration include creams, gels, ointments,salves, patches and transdermal delivery systems.

The compounds according to the invention, in particular the compounds offormula 1, 2, 3, 4, 5 or 6, or the above described pharmaceuticalcompositions comprising one or more compounds of formula 1, 2, 3, 4, 5or 6 may be administered to a subject by any convenient route ofadministration, whether systemically/peripherally or at the site ofdesired action, including but not limited to one or more of: oral (e.g.as a tablet, capsule, or as an ingestible solution), topical (e.g.,transdermal, intranasal, ocular, buccal, and sublingual), parenteral(e.g., using injection techniques or infusion techniques, and including,for example, by injection, e.g. subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, orintrasternal by, e.g., implant of a depot, for example, subcutaneouslyor intramuscularly), pulmonary (e.g., by inhalation or insufflationtherapy using, e.g., an aerosol, e.g. through mouth or nose),gastrointestinal, intrauterine, intraocular, subcutaneous, ophthalmic(including intravitreal or intracameral), rectal, and vaginal.

If said compounds or pharmaceutical compositions are administeredparenterally, then examples of such administration include one or moreof: intravenously, intraarterially, intraperitoneally, intrathecally,intraventricularly, intraurethrally, intrasternally, intracranially,intramuscularly or subcutaneously administering the compoundspharmaceutical compositions, and/or by using infusion techniques. Forparenteral administration, the compounds are best used in the form of asterile aqueous solution which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. The aqueous solutions should be suitably buffered (preferably toa pH of from 3 to 9), if necessary. The preparation of suitableparenteral formulations under sterile conditions is readily accomplishedby standard pharmaceutical techniques well known to those skilled in theart.

Said compounds or pharmaceutical compositions can also be administeredorally in the form of tablets, capsules, ovules, elixirs, solutions orsuspensions, which may contain flavoring or coloring agents, forimmediate-, delayed-, modified-, sustained-, pulsed- orcontrolled-release applications.

The tablets may contain excipients, such as microcrystalline cellulose,lactose, sodium citrate, calcium carbonate, dibasic calcium phosphateand glycine, disintegrants, such as starch (preferably corn, potato ortapioca starch), sodium starch glycolate, croscarmellose sodium andcertain complex silicates, and granulation binders, such aspolyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally,lubricating agents, such as magnesium stearate, stearic acid, glycerylbehenate and talc may be included. Solid compositions of a similar typemay also be employed as fillers in gelatin capsules. Preferredexcipients in this regard include lactose, starch, a cellulose, milksuaar or high molecular weight polyethylene glycols. For aqueoussuspensions and/or elixirs, the agent may be combined with varioussweetening or flavoring agents, coloring matter or dyes, withemulsifying and/or suspending agents and with diluents, such as water,ethanol, propylene glycol and glycerin, and combinations thereof.

Alternatively, said compounds or pharmaceutical compositions can beadministered in the form of a suppository or pessary, or it may beapplied topically in the form of a gel, hydrogel, lotion, solution,cream, ointment or dusting powder. The compounds of the presentinvention may also be dermally or transdermally administered, forexample, by the use of a skin patch.

Said compounds or pharmaceutical compositions may also be administeredby the pulmonary route, rectal routes, or the ocular route. Forophthalmic use, they can be formulated as micronized suspensions inisotonic, pH adjusted, sterile saline, or, preferably, as solutions inisotonic, pH adjusted, sterile saline, optionally in combination with apreservative, such as a benzylalkonium chloride. Alternatively, they maybe formulated in an ointment, such as petrolatum.

For topical application to the skin, said compounds or pharmaceuticalcompositions can be formulated as a suitable ointment containing theactive compound suspended or dissolved in, for example, a mixture withone or more of the following: mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, emulsifying wax and water. Alternatively,they can be formulated as a suitable lotion or cream, suspended ordissolved in, for example, a mixture of one or more of the following:mineral oil, sorbitan monostearate, a polyethylene glycol, liquidparaffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzylalcohol and water.

Typically, a physician will determine the actual dosage which will bemost suitable for an individual subject. The specific dose level andfrequency of dosage for any particular individual subject may be variedand will depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the individual subjectundergoing therapy.

A proposed, yet non-limiting dose of the compounds of formula 1, 2, 3,4, 5 or 6 for administration to a human (of approximately 70 kg bodyweight) may be 0.05 to 5000 mg, preferably 0.1 mg to 1000 mg, of theactive ingredient per unit dose. The unit dose may be administered, forexample, 1 to 4 times per day. The dose will depend on the route ofadministration. It will be appreciated that it may be necessary to makeroutine variations to the dosage depending on the age and weight of thepatient/subject as well as the severity of the condition to be treated.The precise dose and route of administration will ultimately be at thediscretion of the attendant physician or veterinarian.

The compounds of the present invention, including the compounds offormula 1, 2, 3, 4, 5 or 6, may be administered in the context of amonotherapy or in cotherapy with one or more other pharmaceuticalagents. For example, one compound of the present invention or two ormore compounds of the invention may be used in combination with one ormore immunomodulatory drugs and/or anti-inflammatory drugs for thetreatment, prevention or amelioration of an inflammatory, autoimmuneand/or allergic disorder.

A pharmaceutical composition may comprise said compound(s),immunomodulatory drug(s) and/or anti-inflammatory drug(s). Cotherapy mayalso include the administration of two or more compounds of the presentinvention in the absence of further immunomodulatory drugs oranti-inflammatory drugs. It is also envisaged herein that thecompound(s), immunomodulatory drug(s) and/or anti-inflammatory drug(s)might be linked, for example, by formation of conjugates. Accordingly,the compounds, immunomodulatory drugs and/or anti-inflammatory drugs maybe administered to a subject simultaneously. Also, a pharmaceuticalcomposition may comprise only the compound(s) of the present invention,while the one or more immunomodulatory drugs and/or anti-inflammatorydrugs are comprised in a different pharmaceutical composition. In thatcase, it may still be possible to administer the compound(s) of theinvention, immunomodulatory drugs and/or anti-inflammatory drugssimultaneously; however, the compound(s) of the invention may also beadministered before and/or after the one or more immunomodulatory drugsand/or anti-inflammatory drugs. It is readily apparent to a personskilled in the art how to administer, for example, one or more compoundsof the present invention, one or more immunomodulatory drugs, and/or oneor more anti-inflammatory drugs in cotherapy.

It is envisaged that one or more of the compounds as described herein,in particular the compounds of formula 1, 2, 3, 4, 5 or 6, may be usedin combination with one or more immunomodulatory drugs and/or one ormore anti-inflammatory drugs.

The one or more immunomodulatory drugs include, without being limitedthereto: antimetabolites such as, e.g., azathioprine, mycophenolic acid,leflunomide, teriflunomide, or methotrexate; macrolides such as, e.g.,tacrolimus, ciclosporin, or pimecrolimus; IL-2 inhibitors such as, e.g.,abetimus or gusperimus; TNF-α inhibitors such as, e.g., thalidomide orlenalidomide; IL-1 receptor antagonists such as, e.g., anakinra;mammalian target of rapamycin (mTOR) proteins such as, e.g., sirolimus,deforolimus, everolimus, temsirolimus, zotarolimus, or biolimus A9;monoclonal antibodies such as, e.g., eculizumab, infliximab, adalimumab,certolizumab pegol, afelimomab, golimumab, Mepolizumab, omalizumab,nerelimomab, faralimomab, elsilimomab, lebrikizumab, ustekinumab,muromonab-CD3, otelixizumab, teplizumab, visilizumab, clenoliximab,keliximab, zanolimumab, efalizumab, erlizumab, afutuzumab, ocrelizumab,pascolizumab, lumiliximab, teneliximab, toralizumab, aselizumab,galiximab, gavilimomab, ruplizumab, belimumab, ipilimumab, tremelimumab,bertilimumab, lerdelimumab, metelimumab, natalizumab, tocilizumab,odulimomab, basiliximab, daclizumab, inolimomab, zolimomab aritox,atorolimumab, cedelizumab, dorlixizumab, fontolizumab, gantenerumab,gomiliximab, maslimomab, morolimumab, pexelizumab, reslizumab,rovelizumab, siplizumab, talizumab, telimomab aritox, vapaliximab, orvepalimomab; polyclonal antibodies such as, e.g., anti-thymocyteglobulin or anti-lymphocyte globulin; or fusion proteins such as, e.g.,abatacept, belatacept, etanercept, pegsunercept, aflibercept, alefacept,or rilonacept.

Furthermore, the one or more anti-inflammatory drugs include, withoutbeing limited thereto: pyrazolidine or butylpyrazolidine derivativessuch as, e.g., ampyrone, clofezone, kebuzone, metamizole, mofebutazone,oxyphenbutazone, phenazone, phenylbutazone, sulfinpyrazone, orfeprazone; acetic acid derivatives such as, e.g., aceclofenac,acemetacin, alclofenac, bromfenac, bumadizone, bufexamac, diclofenac,difenpiramide, etodolac, fentiazac, indometacin, ketorolac, lonazolac,oxametacin, proglumetacin, sulindac, tolmetin, zomepirac, or amfenac;oxicam derivatives such as, e.g., ampiroxicam, droxicam, lornoxicam,meloxicam, piroxicam, or tenoxicam; propionic acid derivatives such as,e.g., alminoprofen, benoxaprofen, dexibuprofen, dexketoprofen, fenbufen,fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam,indoprofen, ketoprofen, naproxen, oxaprozin, pirprofen, suprofen, ortiaprofenic acid; fenamic acid derivatives such as, e.g., flufenamicacid, meclofenamic acid, mefenamic acid, tolfenamic acid, niflumic acid,morniflumate, or azapropazone; COX-2 inhibitors such as, e.g.,celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, or valdecoxib;or nabumetone, glucosamine, benzydamine, glycosaminoglycan, magnesiumsalicylate, proquazone, superoxide dismutase/orgotein, nimesulide,diacerein, tenidap, oxaceprol, or chondroitin sulfate.

Cotherapy using the compound(s) of the present invention,immunomodulatory drug(s) and/or anti-inflammatory drug(s) may result ina synergistic effect, i.e. the agents acting together may create aneffect greater than that predicted by knowing only the separate effectsof the individual agents. Such a synergistic effect might beparticularly advantageous if less amounts of the compound(s),immunomodulatory drug(s) and/or anti-inflammatory drug(s) may then beused. Thus, possible side-effects of the compound(s), immunomodulatorydrug(s) and/or anti-inflammatory drug(s) might be diminished or avoided.

It is furthermore particularly envisaged that one or more of thecompounds of the invention, in particular the compounds of formula 1, 2,3, 4, 5 or 6, may be used in combination with one or moreimmunomodulatory drugs as described herein above and/or one or moreanti-inflammatory drugs as described herein above (including, forexample, azathioprine, ciclosporin, D-penicillamine, gold salts,hydroxychloroquine, leflunomide, methotrexate, minocycline,sulfasalazine, or cyclophosphamide) for the treatment, prevention oramelioration of rheumatoid arthritis.

The term “treatment of a disorder or disease” as used herein, such as“treatment of an inflammatory, autoimmune and/or allergic disorder”, iswell known in the art. “Treatment of a disorder or disease” implies thata disorder or disease is suspected or has been diagnosed in apatient/subject. A patient/subject suspected of suffering from adisorder or disease typically shows specific clinical and/orpathological symptoms which a skilled person can easily attribute to aspecific pathological condition (i.e., diagnose a disorder or disease).

“Treatment of a disorder or disease” may, for example, lead to a halt inthe progression of the disorder or disease (e.g., no deterioration ofsymptoms) or a delay in the progression of the disorder or disease (incase the halt in progression is of a transient nature only). “Treatmentof a disorder or disease” may also lead to a partial response (e.g.,amelioration of symptoms) or complete response (e.g., disappearance ofsymptoms) of the subject/patient suffering from the disorder or disease.“Amelioration” of a disorder or disease may, for example, lead to a haltin the progression of the disorder or disease or a delay in theprogression of the disorder or disease. Such a partial or completeresponse may be followed by a relapse. It is to be understood that asubject/patient may experience a broad range of responses to a treatment(e.g., the exemplary responses as described herein above).

Treatment of a disorder or disease may, inter alia, comprise curativetreatment (preferably leading to a complete response and eventually tohealing of the disorder or disease) and palliative treatment (includingsymptomatic relief).

Also the term “prevention of a disorder or disease” as used herein, suchas “prevention of an inflammatory, autoimmune and/or allergic disorder”,is well known in the art. For example, a patient/subject suspected ofbeing prone to suffer from a disorder or disease as defined herein may,in particular, benefit from a prevention of the disorder or disease. Thesubject/patient may have a susceptibility or predisposition for adisorder or disease, including but not limited to hereditarypredisposition. Such a predisposition can be determined by standardassays, using, for example, genetic markers or phenotypic indicators. Itis to be understood that a disorder or disease to be prevented inaccordance with the present invention has not been diagnosed or cannotbe diagnosed in the patient/subject (for example, the patient/subjectdoes not show any clinical or pathological symptoms). Thus, the term“prevention” comprises the use of compounds of the present inventionbefore any clinical and/or pathological symptoms are diagnosed ordetermined or can be diagnosed or determined by the attending physician.

The subject or patient, such as the subject in need of treatment,prevention or amelioration, may be a eukaryote, an animal, a vertebrateanimal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, amouse), a murine (e.g. a mouse), a canine (e.g. a dog), a feline (e.g. acat), an equine (e.g. a horse), a primate, a simian (e.g. a monkey orape), a monkey (e.g. a marmoset, a baboon), an ape (e.g. gorilla,chimpanzee, orangutan, gibbon), or a human. The meaning of the terms“eukaryote”, “animal”, “mammal”, etc. is well known in the art and can,for example, be deduced from Wehner and Gehring (1995; Thieme Verlag).In the context of this invention, it is particularly envisaged thatanimals are to be treated which are economically, agronomically orscientifically important. Scientifically important organisms include,but are not limited to, mice, rats, rabbits, fruit flies like Drosophilamelagonaster and nematodes like Caenorhabditis elegans. Non-limitingexamples of agronomically important animals are sheep, cattle and pig,while, for example, cats and dogs may be considered as economicallyimportant animals. Preferably, the subject/patient is a mammal; morepreferably, the subject/patient is a human or a non-human mammal (suchas, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, acat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, achimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig; and inparticular a canine, such as a dog); even more preferably, thesubject/patient is a human.

In this specification, a number of documents including patentapplications and manufacturer's manuals are cited. The disclosure ofthese documents, while not considered relevant for the patentability ofthis invention, is herewith incorporated by reference in its entirety.More specifically, all referenced documents are incorporated byreference to the same extent as if each individual document wasspecifically and individually indicated to be incorporated by reference.

The invention is also described by the following illustrative figures.The appended figures show:

FIG. 1: Inhibition of mast cell degranulation by compounds 1a (FIG. 1A),1b (FIG. 1B), 1c (FIG. 1C), 1d (FIG. 1D), 1e (FIG. 1E) and miltefosine(FIG. 1F). Dose-response curves for inhibition of 8-hexosaminidaserelease from RBL-2H3 cells stimulated with antigen-specific IgE andtriggered with antigen are shown (means±standard error of the mean).

FIG. 2: Inhibition of Akt phosphorylation on Ser473 by compounds 1a(FIG. 2A) and 1c (FIG. 2B). Percentage of total Akt phosphorylated onSer473 is expressed as a percentage of control untreated cells inducedwith IgE and antigen for 15 min (shown are means±standard deviation).

FIG. 3: Effect of compounds 1a and 1c and dexamethasone on mouse earswelling in the DTH response in mice (data are means±standard deviationsof 8 mice; * p<0.01 vs. vehicle control (Dunnett's post hoc test)).

FIG. 4: Effect of compounds 1a and 1c on mouse ear swelling in theallergic contact dermatitis model in mice. FIG. 4A shows a comparison ofthe inhibitory activity of compounds 1a and 1c and miltefosine atdifferent administration times before antigen challenge (data aremeans±SEM of 7 mice; ** p<0.01, *** p<0.001 vs. vehicle control(Dunnett's post hoc test), §p<0.05 vs. vehicle control (t-test)). FIGS.4B and 4C show a comparison of the inhibitory activity of compound 1aand corticosteroids after systemic (oral) application (FIG. 4B) ortopical application (FIG. 4C) (data are means±SEM of 7 mice; ** p<0.01,*** p<0.001 vs. vehicle control (Dunnett's post hoc test)). FIGS. 4D and4E show the local lymph node reaction, comparing the effect of compound1a and topical diflorasone on local lymph node weight (FIG. 4D) and cellnumber (FIG. 4E) (data are means±SEM of 7 mice; ** p<0.01, *** p<0.001vs. vehicle control (Dunnett's post hoc test)).

FIG. 5: Effect of compound 1a on collagen type II-induced arthritis(CIA) in mice. FIG. 5A shows the effects on arthritis score during thecourse of type II CIA of compound 1a and dexamethasone using aprophylactic regimen (data are means of 10-11 mice; * p<0.02, ** p<0.01,*** p<0.001 vs. vehicle control (t-test)). FIG. 5B shows the effects onbody weight changes during the course of type II CIA of compound 1a anddexamethasone using a prophylactic regimen (data are means of 10-11mice; * p<0.02, ** p<0.01, *** p<0.001 vs. vehicle control (t-test)).FIG. 5C shows the effects on arthritis score during the course of typeII CIA of compound 1a using a therapeutic regimen (data are means of 11mice; * p<0.02 vs. vehicle control (t-test)). FIG. 5D shows the effectson spleen and thymus weight during the course of type II CIA of compound1a and dexamethasone using a prophylactic regimen (data are means of10-11 mice; *** p<0.001 vs. vehicle control (t-test)).

FIG. 6: Mean plasma concentration-time profiles (semi-logarithmic) offive polymorphic forms of compound 1a in female Balb/c mice (n=3)following a single oral administration of 100 mg/kg in 0.5%methylcellulose solution.

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention.

EXAMPLES Example 1 Preparation of2-hydroxy-3-(N-methylhexadecylammonio)propane-sulfonate 1a,2-hydroxy-3-(N-methyltetradecylammonio)propanesulfonate 1b and2-hydroxy-3-(N-methyldodecylammonio)propanesulfonate 1c

Sodium-3-chloro-2-hydroxy-1-propanesulfonate (3.83 g, 19.5 mmol),N-methyldodecylamine (3 g, 15 mmol) and N,N-diisopropylethylamine (DIEA)(2.5 g, 19.5 mmol) are suspended in 20 mL of dry dimethylformamide (DMF)and heated to 130° C. under argon atmosphere for 24 h. The volatiles areremoved under reduced pressure and the residue is chromatographed onsilica using dichloromethane/methanol using a stepwise increase ofeluent strength from 9:1 to 4:1. Compound 1c is obtained as whitematerial (4.61 g, 91%).

MS (ESI): 338.2 (M+H⁺), 675.5 (2M+H⁺), 697.5 (2M+Na⁺).

¹H-NMR (300 MHz, CDCl₃): δ=0.81 (t, J=6.9, 3H), 1.1-1.35 (m, 18H), 1.68(m, 2H), 2.89 (d/d, J=4.5/13.1, 3H), 2.95-3.45 (m, 6H), 4.52 (m, 1H),8.90 (br. s, 1H), 9.17 (br. s, 1H).

Compounds 1a and 1b are prepared in a similar way usingN-methylhexadecylamine (for 1a) or N-methyitetradecylamine (for 1b)instead of N-methyldodecylamine.

Examples 2 and 3 Preparation of2-methoxy-3-(N,N-dimethyl-N-tetradecylammonio)-propane-1-sulfonate 1dand 2-acetoxy-3-(N,N-dimethyltetradecylammonio)propanesulfonate 1e

Compound 1b (440 mg, 1.2 mmol), methyl iodide (1.36 g, 9.6 mMol) andK₂CO₃ (497 mg, 3.6 mmol) are suspended in a mixture of acetone (10 mL)and dichloromethane (2 mL). The mixture is stirred at room temperatureovernight. The volatiles are removed under reduced pressure and theresidue is purified by preparative HPLC to yield 287 mg of2-hydroxy-3-(N,N-dimethyl-N-tetradecylammonio)propane-1-sulfonate as awhite solid.

For the preparation of compound 1d sodium hydride (12 mg, 0.52 mmol) issuspended in dry THF (2 mL) under argon atmosphere. The aforementioned2-hydroxy-3-(N,N-dimethyl-N-tetradecylammonio)propane-1-sulfonate (65mg, 0.17 mmol) is dissolved in a mixture of DMF (1 mL) and THF (1 mL)and added dropwise. Methyl iodide (111 mg, 0.78 mmol) is added and themixture is stirred at room temperature for 4 d. The mixture is quenchedwith 0.5 mL of methanol, the solvent is removed under reduced pressureand the residue is purified by preparative HPLC to yield 57 mg (85%) of1d as white material.

MS (ESI): 394.4 (M+H⁺), 787.7 (2M+H⁺).

¹H-NMR (300 MHz, CDCl₃): δ=0.81 (t, J=6.9, 3H), 1.1-1.35 (m, 22H), 1.70(m, 2H), 2.80 (m, 1H), 3.13 (s, 6H), 3.2-3.45 (m, 4H), 3.33 (s, 3H),4.18 (m, 2H).

For the preparation of compound 1e the aforementioned2-hydroxy-3-(N,N-dimethyl-N-tetradecylammonio)propane-1-sulfonate (140mg, 0.37 mmol) and 4-dimethylaminopyridine (DMAP) (3.4 mg, 0.028 mmol)are dissolved in dichloromethane (5 mL) under argon atmosphere. Aceticanhydride (32 mg, 0.31 mmol) and DIEA (40 mg, 0.31 mmol) are added andthe mixture is stirred at room temperature for 24 h. The volatiles areremoved under reduced pressure and the residue is purified bypreparative HPLC to give 123 mg (79%) of 1e as a solid material.

MS (ESI): 422.3 (M+H⁺), 843.6 (2M+H⁺).

¹H-NMR (300 MHz, CDCl₃): δ=0.81 (t, J=6.9, 3H), 1.1-1.35 (m, 22H), 1.69(m, 2H), 2.02 (s, 3H), 3.14 (d, J=5.5, 6H), 3.0-3.3 (m, 4H), 3.69 (m,1H), 4.30 (d/m, J=14.4, 1H), 5.64 (m, 1H).

Example 4 Large Scale Synthesis of Compound 1a

N-methyl hexadecanamide

A suspension of 1775 g of palmitic acid (6.92 mol) and 12.5 L of toluenewas stirred at 20-25° C. and 1245 g (1.5 eq., 10.38 mol)thionyl-chloride added. The reaction mixture was heated under reflux for12 h, then cooled to 20-25° C. and evaporated to dryness on a rotaryevaporator under vacuum (bath temperature, 70° C.). The yield of crudepalmitoyl chloride was 2475 g.

The crude palmitoyl chloride was dissolved in 5.0 L of dichloromethane(DCM), cooled to 0-5° C. and 3.5 L of methylamine (5. 7 eq., 39.44 mol)in 5.8 L of dichloromethane was added dropwise over a period of 105minutes (maintaining the temperature at 5-10° C.). The suspension wasallowed to warm to 20-25° C. and stirred overnight and the mixture thenevaporated to dryness on a rotary evaporator under vacuum (bathtemperature, 40° C.). The residue was suspended in 3.1 L of deionizedwater and the product collected by filtration. The filter cake waswashed with 3.0 L of deionized water and 0.5 L of methylcyclohexane andthen dried to a constant weight in vacuo at 55° C. The yield was 96.0%(1790 g) of a beige powder; GC: 99.3 area %, water content: 0.07%.

Hexadecyl(methyl)amine

To a mixture of 15.75 kg of tetrahydrofuran (THF) and 2.76 kg (1.3 eq.,8.64 mol) lithium aluminium hydride (solution in THF), was added 1.79 kg(6.64 mol) of the N-methyl hexadecanamide in portions, at 20-25° C. (gasevolution). The reaction mixture (a yellowish-brown suspension) wasstirred at reflux for 3 h. The reaction mixture was cooled to 5-10° C.and quenched by dropwise addition of 360 ml of deionized water, 360 mlof 20% sodium hydroxide solution and 1.04 L of deionized water. Tonsil(Süd-Chemie), 370 g, was added to the reaction mixture and the resultingsuspension filtered and the filter cake washed with 2.08 kg of THF. Thefiltrate was evaporated to dryness on a rotary evaporator under vacuum(bath temperature, 60° C.). The yield was 88.0% (1495 g) of an off-whitepowder; GC: 98.2 area %. The material was stored under nitrogen.

2-hydroxy-3-(N-methylhexadecylammonio)propane-sulfonate,sodium/potassium salt (compound 1a)

Batch 1:

Hexadecyl(methyl)amine (814 g, 3.18 mol) was suspended in 10.7 L ofdimethylformamide (DMF). The off-white suspension was stirred at 20-25°C. and 847.5 g (1.3 eq., 4.13 mol) of sodium 3-chloro-2-hydroxypropanesulfonate hemihydrate, 573 g (1.3 eq., 4.13 mol) of potassium carbonateand 99.4 g (0.2 eq., 0.63 mol) of sodium iodide were added. The mixturewas stirred at 50-60° C. for 69 h under nitrogen. HPLC showed 25.1 area% of product in the reaction mixture. DMF was removed by vacuumdistillation (bath temperature, 80° C.) and the residue suspended in4.95 L of THF and evaporated to 1.3 kg of celite. Soxhlet extractionwith 20.0 L of THF:methanol (9:1) was carried out for 4.5 days. Theextract was evaporated to dryness to leave a residue, which wasconfirmed by HPLC to be mostly side-products and which was discarded.The celite was removed from the Soxhlet extractor and dried to constantweight at 60° C. in vacuo. (3220 g). The celite was suspended in 32.0 Lof methanol and heated to reflux. The mixture was filtered hot and thefiltrate crystallized at 0-5° C., yielding 1016 g of yellowish powder(HPLC: 96.6 area %) of compound 1a as the sodium/potassium salt.

Batch 2:

Hexadecyl(methyl)amine (480.8 g, 1.88 mol) was suspended in 6.25 L ofDMF. The off-white suspension was stirred at 20-25° C. and 500 g (1.3eq., 2.44 mol) of sodium 3-chloro-2-hydroxypropane sulfonatehemihydrate, 338.4 g (1.3 eq., 2.44 mol) of potassium carbonate and 58.6g (0.2 eq., 0.37 mol) of sodium iodide were added. The mixture wasstirred at 50-60° C. for 82 h under nitrogen. HPLC showed 30.5 area % ofproduct in the reaction mixture. DMF was removed by vacuum distillation(bath temperature, 80° C.) and the residue crystallized from 12.35 L ofboiling methanol. The mixture was filtered hot (insoluble part: 226.0 g)and the filtrate was crystallized at 0-5° C., yielding 562.0 g ofyellowish powder, (HPLC: 97. 6 area %) of compound 1a as thesodium/potassium salt.

2-hydroxy-3-(N-methylhexadecylammonio)propane-sulfonate (compound 1a)

The sodium/potassium salt, 1100 g, obtained as described above, weresuspended in 11 L of chloroform:methanol (4:1). The pH was adjusted to 5with saturated HCl solution in 2-propanol (the amount of HCl wasdetermined by titration of a sample). Filtration and evaporation todryness yielded 990 g of brownish-yellow, amorphous solid (HPLC: 96.8area %). Crystallization of this solid, as described above, from 8.0 Lof methanol yields 715.0 g of compound 1a (HPLC: 98.6 area %).

Material of this grade was further purified by repeated crystallizationfrom boiling methanol, with removal of insolubles by hot filtration ifrequired. Recrystallization from isopropanol:water (4:1) may also beused. In a typical experiment, 805 g of compound 1a were dissolved in2.4 L of isopropanol:water (4:1) at reflux, slowly cooled to 0-5° C.,filtered and dried to yield 730 g (90% recovery) of compound 1a as anoff-white powder (HPLC: 98.8 area %). In order to obtain a uniformpolymorph, recrystallization from methanol under anhydrous conditions ispreferred for the final crystallization step.

Purification is continued until the following criteria are met:

Purity by HPLC: >99 area %

Residue on ignition: <0.8%

Conductivity of 1% aqueous suspension: <50 μS/cm

NMR, MS: Conform with structure.

Elemental analysis: consistent with composition.

Example 5 Polymorphism of Compound 1a

Compound 1a can be crystallized from a variety of solvents. From apractical standpoint (ease of filtration, low toxicity of solvent),methanol, ethanol and isopropanol are preferred. Addition of 5-25% waterto water-miscible solvents increases solubility and leads to a steepertemperature coefficient of solubility, reducing the amount of solventrequired. Less preferred solvents for recrystallization are 1-propanol,n-butanol, acetone, acetonitrile, THF and ethyl acetate.Recrystallization from water is hard to control and frequently leads todifficulties in filtration.

Starting from dry crude material and solvent, compound 1a is obtained asan anhydrate. Pure monohydrate can be obtained by crystallization fromwater. In a typical procedure, 150 g of compound 1a (anhydrate) wasdissolved in 2 L of deionized boiling water, then seeded with compound1a hydrate and the mixture was allowed to slowly cool to roomtemperature (RT). The precipitate was collected by filtration and driedat 35° C., 15 mbar, yielding 134.6 g (86% recovery) of an off-whitesolid. Karl Fischer titration and elementary analysis indicated thepresence of a monohydrate.

NMR indicates that compound 1a monohydrate remains associated with watereven in solution, leading to an unexpectedly complex pattern of signals.Reversible coalescence is observed upon heating. This water-associatedform is likely to be present under physiological conditions. Theanhydrate shows the expected, simpler NMR spectrum.

Compound 1a monohydrate (batch 2338-CF/30): 1H-NMR (600 MHz, CDCl3):δ=0.87 (t, 3H), [1.15-1.35 (m), 1.31 (br. s), Σ=26H], 1.74 (br. s, 2H),[2.93 (d, J=4.5), 2.98 (d, J=4.7), 2.95-3.35 (m), 3.44 (br. d, J=12.7),Σ=12H], 4.58 (br. s, 1H), 9.21 (br. s, 0.5H), 9.48 (br. s, 0.5H).

Compound is anhydrate (batch 2208-CF/1): 1H-NMR (500 MHz, CDCl3): δ=0.86(t, 3H), [1.15-1.35 (m), 1.30 (br. s), Σ=26H], 1.73 (br. s, 2H), 2.94(s, 3H), [3.05-3.25 (m), 3.12 (d, J=5.7), Σ=5H], 3.39 (br. d, J=12.1,1H), 4.58 (br. d, J=6.1, 1H). (δ>5 ppm: no signals.)

Both the monohydrate from water and the anhydrate from methanol formthin, micrometer-sized platelets of irregular shape. X-ray powderdiffraction (XRPD) indicates a layered structure with a base period of27 A for both forms. Both forms can be easily interconverted. Accordingto differential scanning calorimetry (DSC) analysis, the monohydrateloses its water between 60° C. and 90° C. The anhydrate can be convertedto monohydrate by exposure to air of 100% relative humidity for 4 days.Only one equivalent of water is taken up and the consistency of thematerial remains unchanged.

Crystallization from mixtures of water and water-miscible solventsyielded the anhydrate in most cases. In one experiment with methanolcontaining 10-25% water, formation of monohydrate was observed, but waspoorly reproducible. Due to the more predictable outcome, anhydrousconditions are preferred for the final steps of purification.

A pseudo-polymorph can be characterized by crystallizing compound 1afrom methanol and analyzing the wet material by XRPD. In themethanol-wet sample, a layered structure is observed in which the baseperiod is 28.5 A. During drying at ambient temperature, both 27 A(anhydrate) and 28.5 A are observed together. Upon complete drying atambient temperature, only the diffraction pattern of the anhydrate isobserved. Thus, this crystallization proceeds through the intermediatestage of an instable methanol solvate in which methanol is weaklyintercalated between the layers of the anhydrate structure.

In total, four different polymorphs could be identified by XRPD (Table1). Upon heating, clear solutions could be obtained with water,methanol, ethanol, isopropanol and the solvent:water (9:1) mixtures.Polymorphs from other solvents were obtained by equilibration ofsuspensions of form A in the respective solvents.

TABLE 1 Polymorphs of compound 1a obtained from various solvents. Waterof crystal- Batch Crystal Solvent system lization number form* Water;methanol; acetonitrile: n/a A water (1:1); acetone:water (1:1);ethanol:water (1:1) Solvent:water (9:1); solvents n/a A tested weremethanol, ethanol, isopropanol, THF Water Monohydrate KP-0722.11 AMethanol Anhydrate KP-0726.11 A Methanol; partial sodium salt AnhydrateTN-0382.11 A (alkaline) Methanol:water (1:1) Monohydrate 2338-CF/30 AMethanol, traces of sodium salt Anhydrate 2208-CF/1 A Ethanol;n-butanol; ethylacetate; n/a B THF Acetonitrile n/a C Isopropanol n/a D*Arbitrary nomenclature

Crystal forms A-C are relatively similar and share the same base periodof 27 A. While form A shows two broad reflexions at about 4.0 and 4.4 A,form B shows a single sharp reflexion at about 4.5 A. Form C shows thesame sharp 4.5 A reflexion as form B, plus a complex pattern of fourmore medium broad reflexions between 3.6 and 4.4 A.

Surprisingly, crystallization from neat isopropanol yields a highlycrystalline polymorph which is very different from all other samples inTable 1. In form D, the base period is reduced to 22.8 A and it does notshare any major reflexion with form A. Unlike form A from methanol, thisform does not change during drying. Crystallizing from isopropanolcontaining 10% of water is enough to yield form A instead.

This demonstrates that methanol is to be preferred for the final stepsof crystallization, because it yields a uniform lattice type (form A),even in the presence of small amounts of water. Ease of removal and easeof filtration are also best for methanol. Of form A, both the anhydrateand the monohydrate (which can be prepared by hydration of anhydrate)are suitable for pharmaceutical use. The monohydrate of form A isadvantageous in that it will not take up further water duringstress-testing in stability tests (such as, e.g., open incubation at 40°C./80% humidity for 3 to 6 months). Accordingly, the use of themonohydrate of form A may be preferred in terms of storage stability.

The present invention embraces all polymorphs of the compounds disclosedherein, including the above-described polymorphs of compound 1a.

Example 6 Inhibition of Mast Cell Degranulation Introduction

Mast cells are key effector cells involved in allergic and inflammatorydiseases, and the Rat Basophilic Leukemia clone 2H3 (RBL-2H3) cell lineis a commonly used model of allergen dependent immune modulator release(degranulation) in mast cells. On their surface, they express the highaffinity receptor for IgE (FcεRI). Upon binding of antigen-specific IgEto the receptor, cells become sensitized to the IgE specific antigen(allergen). When IgE-sensitized cells then encounter multivalentantigen, the antigen clusters IgE-FcεRI complexes and initiates a signaltransduction cascade that leads to degranulation, that is, the releaseof inflammatory mediators, such as cytokines, eicosanoids, histamine andenzymes. The assay can be used as a screening method to identifyimmune-modulating compounds, in particular compounds useful in themedical management of allergic and inflammatory diseases and asthma.β-hexosaminidase was previously shown to be released with the samekinetics as histamine (Schwartz et al., J Immunology; 123:1445-1450(1979)), thus offering a simple means to monitor degranulation. TheRBL-2H3 cell line has been successfully used to identify compounds withanti-allergic activity (Choo et al. Planta Med., 69:518-522 (2003)).

Materials and Methods Materials

Chemicals: Rat anti-DNP IgE monoclonal antibody was acquired from Biozol(BZL06936), dinitrophenyl-conjugated human serum albumin (A6661) andTriton X-100 (T9284) were from Sigma-Aldrich,4-methylumbelliferyl-N-acetyl-β-D-glucosaminide (474502),Phorbol-12-myristate-13-acetate (524400) and thapsigargin (586005) fromCalbiochem. Ionomycin (ALX-450-006) was purchased from AlexisBiochemicals. DMSO was from Merck (1.02950.0500) or Sigma-Aldrich(D2650). Cell culture media and supplements, Minimum Essential Medium(21090-022), Minimum Essential Medium without Phenol Red (51200-046),RPMI 1640 Medium (31870-025), L-Glutamine (25030-024) and 0.05%Trypsin-EDTA (25300-054), were obtained from Invitrogen. Fetal bovineserum (A15-151) was from PAA Laboratories. Other reagents were standardlaboratory grade or better.

Buffers and solutions: Phosphate buffered saline (PBS) and 1 M HEPESwere provided by the in-house service facility. Tyrodeis buffer (TyB)consisted of Minimum Essential Medium without Phenol Red supplementedwith 2 mM L-glutamine and 20 mM HEPES. Lysis buffer consisted of 25 mMTris-HCl, pH 7.5, 150 mM NaCl, 5 mM EDTA and 0.1% (w/v) Triton X-100.DNP-HSA was dissolved to 1 mg/ml in water. MUG substrate solutionconsisted of 2.5 mM 4-methylumbelliferyl-N-acetyl-β-D-glucosaminide in0.05 M citrate, pH 4.5; stop solution was 0.1 M NaHCO₃/0.1 M Na₂CO₃, pH10.

Consumables and equipment: For small-volume liquid handling procedures,Rainin LTS electronic pipettes were routinely used (Mettler-Toledo).Costar-Corning 24-well plates (3337) were centrifuged in an Eppendorf5804 R centrifuge. A Heraeus B15 table top incubator was used forincubations at 37° C. under non-sterile conditions. Fluorescence wasmeasured in black Nunc 96-well plates (237105) using a microplate reader(Tecan Safire) or FlexStation 3 (Molecular Devices) multi-mode platereader. Cells were maintained in Hera Cell 240 CO₂ incubators (ThermoScientific). Serological pipettes (4487, 4488 and 4489) and cell cultureflasks (431080) were from Corning-Costar, 1.5 and 2 ml microcentrifugetubes (0030 120.086 and 0030 120.094) were from Eppendorf.

Cell Culture: RBL-2H3 cells obtained from the German Collection ofMicroorganisms and Cell Cultures (ACC312) (Braunschweig, Germany) weremaintained in 70% Minimum Essential Medium with Earle's Salts, 20% RPMI1640 Medium, 10% FBS and 2 mM L-glutamine in 95% air/5% CO₂ at 37° C.and routinely checked for mycoplasma contamination. Cells were passagedevery 3-4 days; after washing cells once with 35 ml PBS cells wereincubated 8 min with 5 ml 0.05% Trypsin-EDTA solution at 37° C. Cellswere removed from the incubator, 15 ml culture medium was added andcells were resuspended by repeated pipetting.

Cell seeding: cells were harvested with Trypsin-EDTA as described and50-100 μl cell suspension seeded into Costar CellBind 24 well clusterplates (no. 3337). Plates were kept for 30 min at RT under the sterilehood before being transferred to the incubator. Cells were used withinone or two days after seeding.

Measurement of β-hexosaminidase release

Experimental Procedures

For sensitization, cells for immediate use were sensitized 6-12 h afterplating; cells to be used the following day were sensitized 26-38 hafter plating. Culture plates were removed from the incubator andchecked for cell growth and contamination. The medium was discarded andcells were sensitized with anti-DNP IgE (0.4 μg/ml) in 0.4 ml culturemedium overnight. Following overnight sensitization, cells were washedwith 0.8 ml pre-warmed TyB and 0.38 ml test compound or vehicle control(supplemented or not with 1% FBS) were added to duplicate wells. Sampleswere adjusted to contain 1% vehicle for test compounds dissolved inorganic solvents. Cells were incubated for 1 h at 37° C. At the end ofthe incubation period, cells were routinely stimulated with 20 μlDNP-HSA (2 μg/ml; final concentration 0.1 μg/ml) diluted in TyB andcells were incubated for 15 min at 37° C. Alternatively, cells werestimulated with 20 μl 5 μM ionomycin (final concentration 0.25 μM) or 20μl 5 μM thapsigargin (final concentration 0.25 μM), both in the absenceor presence of 20 nM PMA (final concentration).

Plates were removed from the incubator and immediately centrifuged at 4°C. for 5 min at 250×g and transferred to an ice bath. Aliquots ofsupernatants, 25 μl, were transferred to 96-well plates. Remainingsupernatant was aspirated from control wells and cells were lysed in 400μl lysis buffer for 5 min at RT on an orbital shaker at 450 rpm undernon-sterile conditions. After lysis, 25 μl aliquots of lysates weretransferred to 96-well plates.

MUG substrate solution, 100 μl, were added to supernatant and lysatesamples and plates were incubated 30 min at 37° C. The reaction wasterminated by addition of 150 μl stop solution. Fluorescence wasmeasured at 365 nm excitation and 440 nm emission wavelengths.

Test compound preparation: test compounds were prepared in 1.5 or 2 mlmicrocentrifuge tubes and incubated for 30 min at 37° C. in aThermomixer Comfort with agitation (750 rpm). An electronic multichannelpipette was used for rapid transfer of compound dilutions frommicrocentrifuge tubes to the cells.

Controls: controls used are defined as follows: negative control,supernatant of unstimulated cells was measured for unspecificβ-hexosaminidase release; positive control, supernatant of DNP-HSAstimulated cells was measured for specific, antigen-stimulated(β-hexosaminidase release; maximum control, lysate of unstimulated cellswas measured for total β-hexosaminidase content.

Assessment of Pharmacologic Effect

Degranulation (β-hexosaminidase release): Degranulation was calculatedas the percentage of β-hexosaminidase released with respect to maximumcontrol (total β-hexosaminidase) after subtraction of negative control(unspecific release) using the formula;

% Degranulation=100×(test compound×negative control)/(maximumcontrol−negative control).

Inhibition of degranulation (inhibition of β-hexosaminidase release):Inhibition of degranulation was calculated as percent reduction ofβ-hexosaminidase release with respect to positive control(antigen-stimulated release) after subtraction of negative control(unspecific release) using the formula;

% Inhibition=100×(1(test compound−negative control)/(positivecontrol−negative control)).

Measurement of Maximum Tolerated Concentration

The maximum tolerated concentration (MTC), i.e. the highestconcentration of test compound that does not cause cytotoxicity, asdetermined by the release of lactate dehydrogenase, was measured overthe tested concentration range. A commercially available cytotoxicitytest was used (Promega Cytotox-One cat. #67891).

The safety index (SI) of a test compound is the ratio between themaximum tolerated concentration and the IC50 and is used as a measure ofthe relative safety of the test compound.

Results

Concentration-dependent inhibition of degranulation was determined forall test compounds over a concentration range, as shown in FIG. 1, andIC50 values (concentration at which 50% of maximal inhibition isreached) were determined for each compound together with the MTC valuesover the same concentration range (Table 2). Results are taken from atleast three independent experiments.

TABLE 2 Inhibition of degranulation: IC50, MTC and SI values CompoundIC50 (μM) MTC (μM) SI 1a 6.9 75 10.9 1b 5.1 100 19.6 1c 4.1 200 48.8 1d3.3 75 22.7 1e 3.9 100 25.6 Miltefosine 4.2 25 6.0

The MTC of the test compounds was 11-50 fold higher than theirrespective IC50s and hence, the inhibition of degranulation can beascribed to a pharmacological effect and not to an effect secondary tocytotoxicity.

All substances outlined in Table 2 show IC50 values in the lowmicromolar range combined with high MTC values when compared toMiltefosine. Thus, the compounds according to the invention and, inparticular compounds 1a to 1e, have an advantageously low cytotoxicity.

Mast cell degranulation is a key cellular event in allergic andinflammatory reactions, in particular in pathological events involvingthe release of mediators such as histamine, leukotrienes andprostaglandins as well as proteases. As consequence, the inhibition ofmast cell degranulation is a valuable strategy for prevention ortreatment of pathological processes involving the aforementionedmediators. Furthermore, the mast cell degranulation assay provides anestimate of the activity of test compounds in other cells that play akey role in the inflammatory response, such as granulocytes, macrophagesand thymocytes, which release proinflammatory cytokines and chemokinesand tissue eroding proteases.

Example 7 Inhibition of Activation of Akt Kinase Introduction

The mast cell degranulation assay using the RBL-2H3 cell line (seeexample 6) was also used to determine the status of the PI3K/Akt axis.Activation of PI3K leads to production of PIP3 on the cytosolic side ofthe lipid bilayer. Akt is recruited to the PIP3 domain and subsequentlyactivated by phosphorylation on residues Ser473 and Thr308. (Franke etal., Cell 81:727-736, (1995)). Once recruited to the membrane, it isphosphorylated and activated by other kinases (Hemmings, Science275:628-630 (1997); Hemmings, Science 276:534 (1997); Downward, Science279:673-674 (1998); Alessi et al., EMBO J. 15:6541-6551 (1996)). Westernblotting of the phosphorylated Ser473 residue on Akt (phospho-AktSer473) is widely used to assess the level of activation of the PI3K/Aktaxis.

Materials and Methods Materials

All buffers and solutions used for the phosphor-Akt Ser473 assay werefrom Meso Scale Discovery. Tris Lysis Buffer consisted of 150 mM NaCl,20 mM Tris, pH 7.5, 1 mM EDTA, 1 mM EGTA and 1% Triton-X-100. CompleteTris Lysis Buffer was prepared prior to use by addition of proteaseinhibitor, phosphatase inhibitors and PMSF. The 10× Tris Wash Bufferconsisted of 500 mM Tris, pH 7.5, 1.5 M NaCl and 0.2% Tween-20. BlockerA was made up of bovine serum albumin in Tris Wash Buffer. Read Buffer Twas used according to manufacturer's instructions. The Whole Cell LysateKits used were phospho-Akt Ser473 (K11100D, Lot K0011749) and totalERK1/2 (K11107D, Lot K0011698) as a loading control.

Equipment

12-well multichannel pipettes (30-300 μl) from Eppendorf were used.Assay plates were agitated on a TiMix 5 control (Edmund Buhler).Electrochemiluminescence detection was performed on a SECTOR Imager 6000(Meso Scale Discovery).

Measurement of Phospho-Akt Ser473 Experimental Procedures

Protein assay: protein concentration was determined using the BCA(bicinchoninic acid) Protein Assay kit according to the manufacturer'sinstructions. Briefly, duplicate 10 μl samples of bovine serum albumin(BSA) standards, blank and lysates were incubated in a 96-well platewith 0.2 ml working reagent for 30 min at 37° C. Plates were cooled toroom temperature for 5 min and absorbance at 562 nm was measured in amulti-mode plate reader. Protein concentrations were calculated usingFlexStation 3 software (SoftMax Pro version 5.3). Protein concentrationof lysates was determined from a standard curve (BSA) using a linearcurve fit.

Phosphoprotein assay: protein phosphorylation was determined using theMULTI-SPOT® Assay System (Meso Scale Discovery), providing simultaneousdetection of phosphorylated and total proteins. Briefly, captureantibodies against phosphorylated and total protein are patterned ondistinct spots in the same well of 96-well plates. Sandwich immunoassayand electrochemiluminescence detection technology are combined tomeasure intensity of the emitted light from phosphorylated and totalprotein spots. Analysis of phosphor-Akt Ser473 was performed accordingto the manufacturer's instructions. The optimal amount of protein wasdetermined at 5 μg lysate per well for ERK1/2 and 10 μg/well forphospho-Akt Ser473. Plates were blocked with 25 μl/well Blocker A for 1h at room temperature with gentle agitation. During this time, thelysates were thawed and diluted to the desired protein concentration incomplete Tris Lysis Buffer. Plates were washed four times in Tris WashBuffer and 25 μl lysate per well added. Plates were incubated for 1-3 hat room temperature with agitation according to the manufacturer'srecommendations. Plates were washed four times with Tris Wash Buffer,followed by addition of 25 μl/well of the respective detection antibodyand incubation for 1 h at room temperature, with agitation. After afinal four washes with Tris Wash Buffer 150 μl/well, Read Buffer T wasadded and plates read on a SECTOR Imager 6000 μlate reader.

Assessment of Effects of Phospho-Akt Ser473

The mean background signal from each plate was subtracted from averagedraw data. The amount of total protein phosphorylated was expressed as %phosphoprotein according to the manufacturer's (Meso Scale Discovery)instructions.

Results

Levels of phospho-Akt Ser473 were determined in IgE sensitized andantigen stimulated cells after treatment without (positive control) orwith 1, 5 and 25 μM test compound and normalized to levels of total Akt.Concentration-dependent inhibition of Akt phosphorylation on Ser473 wasdemonstrated, as shown in FIG. 2. Table 3 shows levels of normalizedphospho-Akt Ser473 as a percentage of those in the positive control.

TABLE 3 Inhibition of Akt phosphorylation on Ser473 by compounds 1a and1c Level of phospho-Akt Ser473 (% positive control) Compound 1 μM 5 μM25 μM 1a  80.8 ± 17.9 62.4 ± 16.1  9.7 ± 4.9 1c 119.7 ± 35.7 67.9 ± 17.317.4 ± 6.4 Percentage of total Akt phosphorylated on Ser473 expressed aspercentage of control untreated cells, after induction with IgE andantigen for 15 min.

A dose-dependent decrease in levels of phospho-Akt Ser473 was observedafter treatment with all compounds outlined in Table 3. Thus, thecompounds according to the invention can be used to reduce levels ofactivated Akt and, accordingly, are useful in the medical interventionin indications in which hyperactivated Akt plays a pathogenic role, suchas inflammatory and allergic diseases, hyperproliferative diseases andother indications.

Example 8 Inhibition of the Delayed-Type Hypersensitivity (DTH) Reactionin Mice Introduction

The anti-inflammatory and anti-allergic effects of compounds 1a and 1cwere assessed in a mouse model of skin delayed-type hypersensitivity(DTH) reactions and compared to a vehicle control and to the referencedrug dexamethasone. DTH reactions are antigen-specific cell-mediatedimmune responses, driven primarily by T helper type 1 (Th1) cells,similar to the tuberculin immunization response. The immune reactioninduced by an ovalbumin challenge to animals previously sensitized withovalbumin in Complete Freund's Adjuvant, is characterized by swelling(edema) at the site of challenge, e.g. the mouse ear. Dexamethasone, ananti-inflammatory steroid, reduces cell-mediated immune responses andwas employed to validate the responsiveness of the assay topharmacological treatment.

Materials and Methods Materials

Ovalbumin (fraction V, lyophilized powder), complete Freud's adjuvant(CFA) and methylcellulose were obtained from Sigma-Aldrich,dexamethasone from Pharmaceutical Works Polfa (Pabianice, Poland).

Animals

Female BALB/cJW mice were bred at the University of Lodz, Lodz, Polandand housed in groups of 8 in makrolon cages with a 12 h light-darkcycle. Mice were given free access to food (Agropol S. j., Motycz,Poland) and water.

Antigen Sensitization and Challenge

Group size was n=8 mice unless otherwise stated. Test compounds werefreshly prepared before administration.

Sensitization: The protein antigen, ovaibumin, was reconstituted in PBSat 4 mg/mi. An ovalbumin-CFA emulsion was prepared by mixing the proteinsolution with the CFA suspension at a ratio of 1:1, using two Luer-locksyringes. The emulsion was tested by putting a drop of emulsion ontoPBS; if the emulsion remained as a tight droplet on the PBS, theemulsion was deemed ready. Mice were sensitized by subcutaneouslyinjecting 25 μL of emulsion into each side of the tail (100 μg ovalbuminper mouse).

Challenge: On the sixth day after sensitization, DTH was elicited bychallenging animals subcutaneously (gauge 30 needle, B. Braun Melsungen,Melsungen, Germany) in the left ears with 10 μL of a 1% suspension ofheat-aggregated ovalbumin (HOVA) (100 μg ovalbumin per mouse). The rightears were administered subcutaneously with PBS and served to determinethe individual differences in ear thicknesses. HOVA was prepared byheating a 5% solution of ovalbumin in saline for 1 h at 80° C. withoccasional swirling. After cooling to room temperature andcentrifugation (400 g, 10 min at 4° C.), the pellet was washed twicewith saline, resuspended at 2% in PBS and aliquots stored at −30° C.Before injection, HOVA was diluted with an equal volume of PBS andsonicated. Ear thickness was measured with a precise spring-loadedcaliper (Art. No. 7309, Mitutoyo, Kawasaki, Japan) before challenge, and24 h after challenge.

Sensitization, challenge and ear thickness measurement were performedunder anesthesia (ketamine 80 mg/kg plus xylazine 8 mg/kg,intraperitoneally).

Compound Administration

The anti-inflammatory effects of compounds 1a and 1c were compared to avehicle control (0.5% methyl cellulose solution) and to the referencedrug, dexamethasone. Test compounds were given at 25 or 100 mg/kg orallyby gavage (Art. No. 432093, Harvard Apparatus GmbH, March-Hugstetten,Germany) 16 h and 3 h before sensitization and then twice daily with thefinal dose given 3 h prior to ear challenge (a total of 14administrations). Dexamethasone was given at 0.1 or 1 mg/kg orally bygavage 3 h before sensitization and once daily with the final dose given3 h prior to antigen challenge (a total of 7 administrations). Alladministrations were given in a volume of 10 mL/kg.

Quantification of Assay Results

To account for individual variability, the increase in right earthickness, before and 24 h after administration of PBS, was subtractedfrom the HOVA-induced increase in left ear thickness. The increase inear thickness was calculated by the difference between ear thicknessbefore and 24 h after antigen challenge. Percent inhibition of earswelling was calculated according to the following formula:

inhibition=100×(IET_(vehicle)−IET_(compound))/IET_(vehicle)

-   -   where        IET=(ET_(24 hrs pc)−ET_(predose))_(HOVA-treated ears)−(ET_(24 hrs pc)−ET_(predose))_(PBS-treated ears)    -   (IET, increase ear thickness; ET, ear thickness; pc, post        challenge)

Statistical Evaluation

Mean and standard deviation (SD) were calculated from individual earedema values. Statistical evaluation was a one-way analysis of variance(ANOVA) with Dunnett's post hoc test or Student's t-test whereappropriate.

Results

Suppression of mouse ear swelling by compounds 1a and 1c as well asdexamethasone, compared to vehicle control is shown in FIG. 3. Table 4summarizes the inhibition of DTH for compounds 1a and 1c.

TABLE 4 Inhibition of mouse ear swelling by compounds 1a and 1c in theDTH response in mice. Inhibition of Compound mouse ear swelling 1a, 25mg/kg 49* 1a, 100 mg/kg 52* 1c, 100 mg/kg 41* Dexamethasone, 0.1 mg/kg14  Dexamethasone, 1.0 mg/kg 53* *p < 0.01 vs. vehicle control(Dunnett's post hoc test)

Dexamethasone administered orally at a dose of 1 mg/kg, once daily overthe whole sensitization period resulted in a significantly reduced DTHresponse, with inhibition of 53%. Such high dosing (overdose) is,however, not suitable for treatment of humans due to severe side effectsof the corticosteroid and was only used to validate the responsivenessof the model. In addition, in the course of the current study, asignificant loss in body weight of 9% (p<0.01 vs. vehicle control withthe paired Student's t-test) was seen in the high dose dexamethasonegroup. A more clinically representative dose of dexamethasone in themouse is 0.1 mg/kg, but at this dose inhibition was very low (14%) anddid not reach significance indicating that only steroid doses whichresult in significant body weight loss upon repeated administration areactive in this model.

Compound 1a, administered orally twice daily over the wholesensitization period at two dosing regimens, 25 mg/kg or 100 mg/kg,reduced the DTH response by 49% and 52%, respectively. The higher doseadministration of compound 1c reduced DTH response by 41%. Hence, thesecompounds were able to produce an inhibition almost equivalent to thatof the high dose of dexamethasone (up to 98% for 1a and 77% for 1c). Incontrast to dexamethasone, no significant toxic side-effects ofcompounds 1a or 1c were observed during the course of the study.

The reduction of DTH response obtained by treatment with compounds 1aand 1c demonstrates that the compounds according to the invention and,in particular compounds 1a and 1c, are effective in the pharmaceuticalintervention in allergic and inflammatory diseases involvingantigen-specific cell-mediated immune responses. Even at the low dose,compound 1a provided for the same high inhibition of the DTH response asobtained by an overdose of dexamethasone, and thus represents aparticularly preferred compound of the present invention.

Example 9 Inhibition of the Allergic Contact Dermatitis InflammatoryResponse in Mice Introduction

The anti-inflammatory and anti-allergic effects of compounds 1a and 1cwere assessed in a mouse model of allergic contact dermatitis, aresponse driven primarily by T helper type 2 (Th2) cells. It has beendemonstrated that BALB/c mice are susceptible to the allergentoluene-2,4-diisocyanate (TOD, producing an inflammatory condition ofthe skin with similar aspects to that of human atopic dermatitis (Baumeret al., J Pharm Pharmacol, 55:1107-1114 (2003); Baumer et al., Br JDermatol. 151:823-830 (2004); Ehinger et al., Eur Pharmacol. 392:93-99(2000)). In this model, an allergic dermatitis response is obtained bysensitizing mice to TDI and subsequently challenging them with antigenby topical administration onto the ears. A quantitative assessment ofanti-inflammatory and anti-allergic effects of topically or orallyadministered test compounds is possible by measuring the resulting earswelling. The advantages of the allergic contact dermatitis model(Zllner et al., Bioessays 26:693-6 (2004)) are reproducibility andreliability (>90% of BALB/c mice respond to sensitization), a shortinduction protocol, quantitative assessment by measuring ear thickness,atopic dermatitis-like skin lesions can be induced, and clinicallyrelevant pharmaceuticals, such as corticosteroids,calcineurin-inhibitors and PDE4-inhibitors, are effective in this model.

Materials and Methods Materials

Dexamethasone dihydrogenphosphate (Dexa-Inject) was obtained from MibeGmbH, Jena, Germany and diflorasone diacetate from Basotherm, Biberachan der Diss, Germany.

Animals

Female BALB/c-mice were obtained from Charles River (Sulzfeld, Germany)at age 8 weeks. All animals were housed in groups of eight per cage at22° C. with a 12 h light/dark-cycle. Water and a standard diet(Altromin, Lage/Lippe, Germany) were available ad libitum. All animalswere acclimatized for one week before experimental procedures werecommenced.

TDI Sensitization, Allergen Challenge and Mouse Ear Swelling Test

Experimental procedures for BALB/c mice housing, TDI sensitization andchallenge, and measurement of ear thickness were performed as previouslydescribed (Baumer et al., J Pharm Pharmacol. 55:1107-1114 (2003)) withthe following modifications. For active sensitization, 100 μL of 5%(w/v) TDI was administered to the shaved and stripped abdominalepidermis on day one, and for the next three consecutive days, 50 μL of5% (w/v) TDI was applied. The allergic reaction was boosted 21 dayslater by application of 50 μL of 0.5% (w/v) TDI. For the examination oftest compound effects, the left ears were used for the TDI challenge (20μL of 0.5% in acetone) and ear thickness measured 3 h before and 24 hafter challenge.

Compound Administration for Systemic Treatment

Group size was n=7 mice unless otherwise stated. Test compounds werefreshly prepared before administration.

Administration time: to determine optimal time for administrationtreatment groups were treated orally by gavage with 100 mg/kg ofcompound 1a or 1c (suspended in 0.5% tylose, 10 mL/kg) 1, 4 or 16 hbefore topical TDI challenge. One group was treated with 100 mg/kgmiltefosine orally, 16 h before challenge (based on available data foroptimal administration time for miltefosine) and vehicle treated micereceived tylose (10 mL/kg) orally, 4 h before challenge.

Dose-response: two groups of mice were treated orally with compound 1aat 25 mg/kg or 100 mg/kg suspended in 0.5 tylose, 4 h before topical TDIchallenge. Vehicle treated mice received 0.5% tyiose orally 4 h beforechallenge. As a positive control, dexamethasone was administered insaline solution at 1 mg/kg or 3 mg/kg, 2 h and 30 min before challengeand 1 h after challenge. The dose and dosing scheme for dexamethasonewas based on previous experience showing a maximal effect in this model.

Compound Administration for Topical Treatment

Compound 1a was administered to two groups of mice topically in 20 μl ofa 2% or 6% solution in propyleneglycol. The suspension was heated to 60°C. and mixed using a thermomixer (Eppendorf) until it became clear. Thesolution was applied, 2 h before topical TDI challenge by administrationof 10 μl onto each of the inner and outer surfaces of the left ears. Avehicle group (n=5) was treated with propyleneglycol. As a positivecontrol, diflorasone diacetate was administered at 0.01% (low dose) and0.05% (high dose) in 20 μl acetone, 2 h before challenge. A basalcontrol group was left untreated.

Determination of Local Lymph Node Weight and Cell Count

Directly after sacrifice, the ear draining lymph node (Ln. auricularis)was prepared and excised. Organ weight was determined by means of ananalytical balance (Kern, Balingen, Germany). Single cell suspensionswere prepared by means of a glass potter (VWR, Darmstadt, Germany) andcells were counted with a hemocytometer (Neubauer, VWR, Germany).

Statistical Evaluation

Mean and standard error of the mean (SEM) were calculated fromindividual ear edema values. Statistical evaluation was a one-wayanalysis of variance (ANOVA) (if the test for normal distribution waspassed) or the Kruskal-Wallis one-way ANOVA on Ranks (if the normaldistribution test failed). Both were followed by a post-hoc test(Dunnett's method or Dunn's test, respectively). A p<0.05 was consideredto be significant.

Results

Suppression of mouse ear swelling by compounds 1a and 1c after oraladministration, compared to vehicle control is shown in FIG. 4A. Table 5summarizes inhibition of the allergic contact dermatitis response bycompounds 1a and 1c.

TABLE 5 Effect of orally administered compounds 1a and 1c on earswelling in the allergic contact dermatitis response in mice. Inhibitionof Compound mouse ear swelling Administration time (oral) 1a, 100 mg/kg,1 h 72.6*** 1a, 100 mg/kg, 4 h 73.4*** 1a, 100 mg/kg, 16 h 29.0 1c, 100mg/kg, 1 h 58.1** 1c, 100 mg/kg, 4 h 68.5*** 1c, 100 mg/kg, 16 h42.7^(§) Miltefosine, 100 mg/kg, 16 h 47.3^(§) Dose-response (oral) 1a,25 mg/kg 44.9*** 1a, 100 mg/kg 44.4*** Dexamethasone, 1 mg/kg 78.6***Dexamethasone, 3 mg/kg 87.1*** **p < 0.01, ***p < 0.001 vs. vehiclecontrol (Dunnett's post hoc test) compared to vehicle, ^(§)p < 0.05 vs.vehicle control (t-test)

In the administration time study with oral administration, compounds 1aand 1c reduced ear swelling significantly (up to 73% of vehicle control)when administered 1 h or 4 h before challenge, as also shown in FIG. 4A.Miltefosine has previously been shown to be maximally effective afteroral administration when given 16 h before challenge and also in thisstudy significantly reduced ear swelling (47% of vehicle control).However, miltefosine was not as maximally effectively as compounds 1aand 1c at their optimal administration time of 4 h, reaching only 64% ofthe inhibitory efficacy of 1a and 69% of that of compound 1c.

In the dose-response study, compound 1a administered 4 h beforechallenge reduced ear swelling significantly (45%) at 25 or 100 mg/kg,as shown in FIG. 4B. In comparison, dexamethasone administered orally atdoses of 1 and 3 mg/kg significantly inhibited ear swelling (78 and 87%respectively). As discussed in example 8 for the DTH response, such highdoses (overdose) of dexamethasone are unsuitable for treatment of humansdue to severe side effects of the corticosteroid and were used tovalidate the responsiveness of the model. Nevertheless, compound 1a wasable to effect an inhibition equal to 52% of the highest dose ofdexamethasone at doses of 1a, which showed no toxicity.

Compounds 1a (25 mg/kg and 100 mg/kg) and 1c (100 mg/kg) had asignificant impact on the TDI induced inflammatory reaction. Thus, thecompounds according to the invention and, in particular compound 1a and1c, are particularly effective and thus useful for the oralpharmaceutical intervention in inflammatory diseases, in particular inatopic dermatitis.

Suppression of mouse ear swelling by compounds 1a and 1c after topicaladministration, compared to vehicle control is shown in FIG. 4C. Table 6summarizes inhibition of the allergic contact dermatitis response bycompounds 1a and 1c.

TABLE 6 Effect of topically administered compound 1a on ear swelling inthe allergic contact dermatitis response in mice. Inhibition of Compoundmouse ear swelling 1a, 2% 67.9** 1a, 6% 63.1** Diflorasone, 0.1%101.1*** Diflorasone, 0.5% 110.8*** **p < 0.01, ***p < 0.001 vs. vehiclecontrol (Dunnett's post hoc test) compared to vehicle. Diflorasonetreatment reduced ear thickness below that of untreated mice.

Compound 1a topically administered as a solution at 2% or 6%significantly reduced ear swelling up to 68%, compared to vehiclecontrol. The positive control, diflorasone, completely eliminated earswelling and even reduced ear thickness to below the level of untreatedmice. This indicates that the doses of diflorasone used here are notrepresentative of a clinical benchmark, but were used to validate theresponsiveness of the model. It must also be stressed, that diflorasoneis one of the strongest dermal corticosteroids and is taken for severeeczema.

One of the most undesirable side-effects of corticosteroidadministration is immunosuppression, which leads to the inability toeffectively address parasitic infection, wound healing and tumor growth.In the current study, the local lymph node reaction after TDI challenge(lymph node weight and cell number) was determined to assess theresponse of immune organs. Diflorasone produced a highly significantreduction in the local lymph node reaction at both 0.1% and 0.5%, bycompletely inhibiting the increase in lymph node weight and cell number(FIGS. 4D and 4E), even reducing this to levels below untreated animals.In contrast, topical treatment with compound 1a at 2% or 6% did not haveany impact on the local lymph node reaction (FIGS. 4D and 4E).

In view of the strong effect shown in the allergic contact dermatitismodel, the compounds of the present invention and, including compound1a, are particularly effective and thus useful for the topicalpharmaceutical intervention in inflammatory diseases, in particular inatopic dermatitis. In addition, the compounds of the present invention,including compound 1a, do not show adverse effects typical of topicallyadministered corticosteroids, such as inhibition of the lymph nodereaction and loss in body weight.

Example 10 Inhibition of Collagen Type II-Induced Arthritis (CIA) in theMouse Introduction

The inhibitory effect of compound 1a was assessed for anti-inflammatoryand anti-arthritic activity in the type II collagen-induced arthritis(CIA) model in the mouse. CIA has been proposed as a pertinent animalmodel of rheumatoid arthritis in humans. In this model, a peripheralarthritis is elicited by intradermal injection of homologous orheterologous (e.g. bovine, chicken) type II collagen (CII) in completeFreund's adjuvant (CFA) into rats or mice (Stuart et al., Ann RevImmunol. 2:199-218 (1984); Marty et al., J Clin Invest. 107:631-640(2001); Boissier et al., Eur J Immunol. 25:1184-90 (1995)). The centralrole played by T cells in the development of type II CIA is demonstratedby the T cell proliferative response to mouse CII in immunized mice, thesuccessful adoptive transfer of the disease with immune cells from thespleen, and the resistance of athymic nude mice to the induction of thepathology (Stuart et al., Ann Rev Immunol. 2:199-218 (1984); Marty etal., J Clin Invest. 107:631-640 (2001)). An advantage of this model ofarthritis as compared to others is the development of an arthritogenicresponse toward a well defined antigen (CII), which also permits thestudy of antigen-induced immunological phenomena and their selectivemodification by immunopharmacological intervention.

Materials and Methods Materials

Bovine type II collagen (Chondrex, Redmond Wash., USA) was dissolved at2 mg/ml in 0.05 M acetic acid by gentle stirring overnight at 4° C. CFAwas prepared by adding Mycobacterium tuberculosis H37Ra (Difco, Detroit,Mich.)) at 2 mg/ml to IFA (incomplete Freund's adjuvant, Sigma Aldrich,Milano, Italy). Before injection, CII was emulsified with an equalvolume of CFA.

Animals

Eight to 9 week old male DBA/1j mice were purchased from HarlanLaboratories srl (San Pietro al Natisone, Udine, Italy) and kept understandard laboratory conditions with free access to food and water. Micewere allowed to adapt one week to their environment before starting thestudy.

Induction of Collagen Induced Arthritis (CIA)

Group size was n=11 mice unless otherwise stated. Test compounds werefreshly prepared before administration. Mice were injected intradermallyat the base of the tail with 100 μL of an emulsion containing 100 μg ofCII, IFA and 100 μg of Mycobacterium tuberculosis. On day 21, a boost ofCII in IFA was administered.

Prophylactic Treatment

Five groups of mice were treated under a prophylactic regimen from day 0to 47 and an additional group of sham treated mice was treated only withthe CII vehicle, on days 0 and 21. Compound 1a was administered as asuspension in 0.5% carboxymethylcellulose (10 mL/kg) and, as a positivecontrol, dexamethasone was administered at 0.3 mg/kg as detailed below:

Group 1: compound 1a at 25 mg/kg, orally by gavage, twice dailyGroup 2: compound 1a at 100 mg/kg, orally by gavage, twice dailyGroup 3: dexamethasone 0.3 mg/kg, intraperitoneally, once dailyGroup 4: vehicle (carboxymethylcellulose), orally by gavageGroup 5: sham treated miceAnimals were sacrificed on day 47 after immunization.

Therapeutic Treatment

Groups of mice were treated with compound 1a from the onset of arthriticsymptoms, defined as first day on which a disease score of 1 or higherwas observed and mice expressing the respective disease score wererandomly assigned to each experimental group. Treatment was continuedfor 20 consecutive days.

Group 6: compound 1a at 100 mg/kg, orally by gavage, twice daily

As the treatment was based on the individual expression of arthritissymptoms, the mice were synchronized to the first day of treatment forevaluation of the disease progression. No separate vehicle group wasincluded for the therapeutic treatment regimen hence vehicle group 4 wasreanalyzed after synchronization to the first day on which a diseasescore of 1 or higher was observed. Animals were sacrificed after 20 daysof treatment.

Clinical Assessment

Mice were evaluated for arthritis daily by an observer unaware of thetreatment regimens according to a macroscopic scoring system: 0=no signsof arthritis; 1=swelling and/or redness of the paw or one digit;2=involvement of 2 joints; 3=involvement of more than 2 joints; 4=severearthritis of the entire paw and digits. An arthritis index wascalculated for each mouse by summing the scores for individual paws.Clinical severity was also determined by evaluation of paw thickness ofboth front and hind-paws using a thickness gauge. An index wascalculated for each mouse by summing the thickness for individual paws.Body weights were also recorded daily.

Statistical Evaluation

Mean and standard deviation (SD) were calculated from individual scorevalues.

For the arthritis score two different statistical calculations wereperformed. For each treatment day the arthritis scores of each groupwere compared to the vehicle control group using the student's-t testand a p<0.05 was considered significant.

Additionally, a cumulative arthritis score was calculated for eachtreatment group by summing all arthritis scores throughout the studyperiod. The cumulative arthritis scores were compared using thestudent's-t test and a p<0.05 was considered significant. The cumulativearthritis score requires that all animals are evaluated for the samelength of time; in order to determine the cumulative arthritis score ofanimals which had died during the study, the missing values weresubstituted with the group mean for the day of the missing value. Thesubstitution of missing values was only performed for the cumulativearthritis score and not used for other calculations.

Results Effects of the Prophylactic Treatment of Test Compounds onArthritic Score

As expected, starting 5-6 days after the CII boost, clinical signs ofarthritis became observable in vehicle treated control mice, consistingof progressively augmenting arthritic scores, accompanied by increasedpaw thickness. Significant loss in body weight of vehicle treatedanimals compared to the sham-treated group was observed after the CIIboost.

Compound 1a reduced the cumulative arthritis score and paw thickness atboth 25 and 100 mg/kg compared to vehicle treated mice, as shown in FIG.5A. Dexamethasone nearly completely suppressed the clinical signs ofarthritis, but also induced a significant reduction in body weight fromday 8 until the end of the study, when compared to vehicle treated mice(FIG. 5B). However, no effects on body weight were observed in micetreated with compound 1a at both low and high doses (FIG. 5B).

Effects of the Therapeutic Treatment of Test Compounds on ArthriticScore

Compound 1a at 100 mg/kg significantly reduced the arthritis score andthe cumulative arthritis score compared to vehicle-treated mice from day11 to 13 and on day 21, as also shown in FIG. 5C. Furthermore, a trendto a reduction in the duration of disease compared to vehicle-treatedmice was observed.

Immune Organ Weights

At sacrifice, thymuses and spleens were collected and weighed to assessthe effect on these important immune organs. Compared to thesham-treated mice, animals treated with the vehicle exhibited asignificant increase in spleen weight, due to the proliferation oflymphocytes in answer to elicitation by CII injection. As expected,treatment with the positive control drug, dexamethasone, markedlyreduced the weights of both spleens and thymuses compared to bothvehicle treated and sham groups demonstrating the knownimmunosuppressive effect of corticosteroids (FIG. 5D). In contrast,treatment with compound 1a did not reduce thymus or spleen weightscompared to vehicle treated mice (FIG. 5D).

The data demonstrate that compound 1a ameliorated the clinical course oftype II CIA when administered prophylactically, reducing the arthritisscore and paw thickness. When administered under the therapeuticregimen, 1a a significant reduction in the cumulative disease score wasevidenced. Compound 1a did not show any toxic effects, whereasdexamethasone caused a significant loss in body weight and spleen andthymus weights. These results suggest that the compounds of the presentinvention, including compound 1a, are particularly effective and thususeful for the medical intervention in rheumatoid arthritis.

Example 11 Pharmacokinetic Study of Five Different Batches of Compound1a after a Single Oral Administration to Mice Introduction

The aim of the study was to evaluate pharmacokinetic (PK) properties offive different batches including anydrates and monohydrates of thecrystal form A of compound 1a (cf. Table 1 in Example 5) after a singleoral administration to mice. Three of the forms were anhydrous and twowere monohydrates.

Materials and Methods

Compound 1a was administered as a suspension of 0.5% methyl cellulose(Sigma-Aldrich) in water at a dose of 100 mg/kg (10 ml/kg) by oralgavage to non-fasted female Balb/c mice (n=3). This dose had previouslybeen shown to be well tolerated. No overt toxicity was shown regardlessof the polymorphic crystal form.

Blood was collected by decapitation at 0.5, 1, 2, 4, 8, 12, 24, and 48 hafter administration. Blood plasma was isolated by centrifugation at 4°C. (20,000×g for 10 min), transferred to microtubes containinglithium-heparin and frozen in aliquots at −70° C. until assayed bymass-spectrometry. Mean plasma concentration-time profiles(semi-logarithmic) of the five polymorphic crystal forms of compound 1aare shown in FIG. 6.

Pharmacokinetic Parameters

For PK evaluation, summary statistics and plotting of concentration/timecurves, all values below the lower limit of quantification (LLOQ) wereset to zero. PK parameters for the five forms of compound 1a are listedin Table 7.

TABLE 7 Pharmacokinetic parameters of polymorphic forms of compound 1ain female Balb/c mice (n = 3) following a single oral administration of100 mg/kg in 0.5% methylcellulose solution. Polymorphic form PK 2338-2208- KP- KP- TN- parameter CF/30 CF/1 0722.11 0726.11 0382.11 c_(max)(ng/ml) 1063 1003 571 759 627 t_(max) (h) 1.0 1.0 2.0 1.0 1.0 c_(last)(ng/ml) 1.8 1.1 3.8 1.2 3.4 t_(last) (h) 48.0 48.0 24.0 48.0 24.0AUC_(0-t) (ng*h/ml) 3118 4400 3162 3744 3535 AUC_(0-inf) (ng*h/ml) 31444412 3179 3758 3547 MRT (h) 5.5 5.0 4.8 5.5 5.9 t_(1/2) (h) 9.9 7.3 n.d.8.2 n.d. c_(max) Observed maximum plasma concentration t_(max) Time ofoccurrence of c_(max) c_(last) Concentration at last sampling time pointt_(last) Time of last sampling time point AUC_(0-t) Area under theplasma concentration versus time curve from time zero to t_(last),calculated by the trapezoidal rule AUC_(0-inf) Area under the plasmaconcentration versus time curve from time zero to infinity withextrapolation of the terminal phase MRT Mean residence time calculatedusing trapezoid area calculations extrapolated to infinity t_(1/2)Terminal half-life

The PK behaviour was comparable for all polymorphic forms of compound1a. The compound was rapidly absorbed from the gastro-intestinal(GI)-tract, reaching a maximum plasma concentration after 1-2 h. Theoverall exposure was highest with form 2208-CF/1. A second plasma peakwas observed at 8 h after administration of forms KP-0726.11 andTN-0382.11, indicating a second absorption window that might be causedby improved solubility of these polymorphs in the lower part of theGI-tract. The mean residence time was in the same range for allpolymorphic forms tested and the PK curves and terminal half-lives weresimilar between 8-24 h, as also shown in FIG. 6. No terminal half-liveswere determined for KP-0722.11 or TN-0382.11, due to the lack of 48 hvalues for these forms.

1. A compound of the following formula 1

wherein: R¹ is a C₁₀₋₂₀ hydrocarbon group; R² is a C₁₋₄ alkyl group, and R³ is —H, a C₁₋₄ alkyl group or R³ is absent; or R² and R³ are mutually linked to form a pyrrolidine ring, a piperidine ring or an azepane ring together with the nitrogen atom X to which they are attached, wherein said pyrrolidine ring, said piperidine ring or said azepane ring is optionally substituted with one or more groups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or -alkyl)(C₁₋₃ alkyl); R⁴ is a C₃₋₆ alkylene group which is substituted with one or more groups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH; R⁵ is —SO₃ ⁻, —SO₃H, —PO₃H⁻, —PO₃ ²⁻, —PO₃H₂, —PO₂(OC₁₋₃ alkyl)⁻, —PO₂H(OC₁₋₃ alkyl), —PO(OC₁₋₃ alkyl)₂, —CO₂ ⁻, —CO₂H or —CO₂(C₁₋₃ alkyl); and X is N⁺ or, if R³ is absent, X is N; or a pharmaceutically acceptable salt, solvate or prodrug thereof for use in the treatment, prevention or amelioration of an inflammatory, autoimmune and/or allergic disorder selected from: psoriasis, atopic dermatitis (atopic eczema), contact dermatitis, xerotic eczema, seborrheic dermatitis, neurodermitis, dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis (Duhring's Disease), autoeczematization, dermatomyositis, hyper-IgE (Buckley) syndrome, Wiskott-Aldrich syndrome, anaphylaxis, food allergy, allergic reactions to venomous stings, acute urticarias, chronic urticarias, physical urticarias including aquagenic urticaria, cholinergic urticaria, cold urticaria (chronic cold urticaria), delayed pressure urticaria, dermatographic urticaria, heat urticaria, solar urticaria, vibration urticaria, adrenergic urticaria, urticaria angioedema, inflammatory bowel disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, diversion colitis (diverticulitis), Behçet's syndrome, indeterminate colitis, celiac disease, irritable bowel syndrome, post-operative ileus, eosinophilic gastroenteropathy, gastritis, chronic allergic rhinitis, seasonal allergic rhinitis (hay-fever), allergic conjunctivitis, chemical conjunctivitis, neonatal conjunctivitis, Sjögren syndrome, open-angle glaucoma, dry eye disease, diabetic macular edema, chronic obstructive pulmonary disease (COPD), allergic asthma, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, lung fibrosis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, reactive arthritis, polymyalgia rheumatica, Guillain-Barre syndrome, Hashimoto's thyroiditis, Grave's disease, temporal arteritis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, alopecia areata, a graft-versus-host disease, a host-versus-graft disease, or a transplant rejection.
 2. The compound for use according to claim 1, wherein R⁵ is SO₃ ⁻ or SO₃H.
 3. The compound for use according to claim 1, wherein R⁵ is —PO₃ ²⁻, —PO₃H⁻, or —PO₃H₂.
 4. The compound for use according to any of claims 1 to 3, wherein R⁴ is —CH₂—CH(—R⁴¹)—CH₂— and R⁴¹ is selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH.
 5. The compound for use according to any of claims 1 to 4, wherein R¹ is a linear C₁₀₋₂₀ alkyl group, a linear C₁₀₋₂₀ alkenyl group, or a linear C₁₀₋₂₀ alkynyl group.
 6. The compound for use according to any of claims 1 to 5, wherein R¹ is —(CH₂)₁₁—CH₃, —(CH₂)₁₃—CH₃, or —(CH₂)₁₅—CH₃.
 7. The compound for use according to any of claims 1 to 6, wherein R² is methyl, and R³ is —H, methyl or R³ is absent.
 8. The compound for use according to any of claims 1 to 6, wherein R² and R³ are mutually linked to form a piperidine ring together with the nitrogen atom X to which they are attached, wherein the piperidine ring is optionally substituted with —OH.
 9. The compound for use according to claim 1, wherein the compound is a compound of the following formula 2

wherein: R¹ is a C₁₀₋₂₀ hydrocarbon group; R⁴ is a C₃₋₆ alkylene group which is substituted with one or more groups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH; R⁵ is —SO₃ ⁻, —SO₃H, —PO₃H⁻, —PO₃ ²⁻, —PO₃H₂, —PO₂(OC₁₋₃ alkyl)⁻, —PO₂H(OC₁₋₃ alkyl), —PO(OC₁₋₃ alkyl)₂, —CO₂ ⁻, —CO₂H or —CO₂(C₁₋₃ alkyl); each R⁶ is independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃ alkyl)(C₁₋₃ alkyl); n is 1, 2, or 3; and m is an integer from 0 to 4; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 10. The compound for use according to claim 1, wherein the compound is a compound of the formula 1a, 1b, 1c, 1d, or 1e

or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 11. A pharmaceutical composition comprising the compound of any of claims 1 to 10 and a pharmaceutically acceptable excipient for use in the treatment, prevention or amelioration of an inflammatory, autoimmune and/or allergic disorder selected from: psoriasis, atopic dermatitis (atopic eczema), contact dermatitis, xerotic eczema, seborrheic dermatitis, neurodermitis, dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis (Duhring's Disease), autoeczematization, dermatomyositis, hyper-IgE (Buckley) syndrome, Wiskott-Aldrich syndrome, anaphylaxis, food allergy, allergic reactions to venomous stings, acute urticarias, chronic urticarias, physical urticarias including aquagenic urticaria, cholinergic urticaria, cold urticaria (chronic cold urticaria), delayed pressure urticaria, dermatographic urticaria, heat urticaria, solar urticaria, vibration urticaria, adrenergic urticaria, urticaria angioedema, inflammatory bowel disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, diversion colitis (diverticulitis), Behçet's syndrome, indeterminate colitis, celiac disease, irritable bowel syndrome, post-operative ileus, eosinophilic gastroenteropathy, gastritis, chronic allergic rhinitis, seasonal allergic rhinitis (hay-fever), allergic conjunctivitis, chemical conjunctivitis, neonatal conjunctivitis, Sjögren syndrome, open-angle glaucoma, dry eye disease, diabetic macular edema, chronic obstructive pulmonary disease (COPD), allergic asthma, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, lung fibrosis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, reactive arthritis, polymyalgia rheumatica, Guillain-Barre syndrome, Hashimoto's thyroiditis, Grave's disease, temporal arteritis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, alopecia areata, a graft-versus-host disease, a host-versus-graft disease, or a transplant rejection.
 12. A method of treating, preventing or ameliorating an inflammatory, autoimmune and/or allergic disorder, the method comprising the administration of the compound of any of claims 1 to 10 or the pharmaceutical composition of claim 11 to a subject in need of such a treatment, prevention or amelioration, wherein said inflammatory, autoimmune and/or allergic disorder is selected from: psoriasis, atopic dermatitis (atopic eczema), contact dermatitis, xerotic eczema, seborrheic dermatitis, neurodermitis, dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis (Duhring's Disease), autoeczematization, dermatomyositis, hyper-IgE (Buckley) syndrome, Wiskott-Aldrich syndrome, anaphylaxis, food allergy, allergic reactions to venomous stings, acute urticarias, chronic urticarias, physical urticarias including aquagenic urticaria, cholinergic urticaria, cold urticaria (chronic cold urticaria), delayed pressure urticaria, dermatographic urticaria, heat urticaria, solar urticaria, vibration urticaria, adrenergic urticaria, urticaria angioedema, inflammatory bowel disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, diversion colitis (diverticulitis), Behçet's syndrome, indeterminate colitis, celiac disease, irritable bowel syndrome, post-operative ileus, eosinophilic gastroenteropathy, gastritis, chronic allergic rhinitis, seasonal allergic rhinitis (hay-fever), allergic conjunctivitis, chemical conjunctivitis, neonatal conjunctivitis, Sjögren syndrome, open-angle glaucoma, dry eye disease, diabetic macular edema, chronic obstructive pulmonary disease (COPD), allergic asthma, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, lung fibrosis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, reactive arthritis, polymyalgia rheumatica, Guillain-Barre syndrome, Hashimoto's thyroiditis, Grave's disease, temporal arteritis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, alopecia areata, a graft-versus-host disease, a host-versus-graft disease, or a transplant rejection.
 13. The compound for use according to any of claims 1 to 10 or the pharmaceutical composition for use according to claim 11 or the method of claim 12, wherein said inflammatory, autoimmune and/or allergic disorder is selected from psoriasis, atopic dermatitis (atopic eczema), contact dermatitis, xerotic eczema, seborrheic dermatitis, neurodermitis, dyshidrosis, discoid eczema, venous eczema, dermatitis herpetiformis (Duhring's Disease), autoeczematization, dermatomyositis, hyper-IgE (Buckley) syndrome, Wiskott-Aldrich syndrome, anaphylaxis, food allergy, or allergic reactions to venomous stings.
 14. The compound for use according to any of claims 1 to 10 or the pharmaceutical composition for use according to claim 11 or the method of claim 12, wherein said inflammatory, autoimmune and/or allergic disorder is selected from acute urticarias, chronic urticarias, physical urticarias including aquagenic urticaria, cholinergic urticaria, cold urticaria (chronic cold urticaria), delayed pressure urticaria, dermatographic urticaria, heat urticaria, solar urticaria, vibration urticaria, adrenergic urticaria, or urticaria angioedema.
 15. The compound for use according to any of claims 1 to 10 or the pharmaceutical composition for use according to claim 11 or the method of claim 12, wherein said inflammatory, autoimmune and/or allergic disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, diversion colitis (diverticulitis). Behçet's syndrome, indeterminate colitis, celiac disease, irritable bowel syndrome, post-operative ileus, eosinophilic gastroenteropathy, or gastritis.
 16. The compound for use according to any of claims 1 to 10 or the pharmaceutical composition for use according to claim 11 or the method of claim 12, wherein said inflammatory, autoimmune and/or allergic disorder is selected from chronic allergic rhinitis, seasonal allergic rhinitis (hay-fever), allergic conjunctivitis, chemical conjunctivitis, neonatal conjunctivitis, Sjögren syndrome, open-angle glaucoma, dry eye disease, or diabetic macular edema.
 17. The compound for use according to any of claims 1 to 10 or the pharmaceutical composition for use according to claim 11 or the method of claim 12, wherein said inflammatory, autoimmune and/or allergic disorder is selected from chronic obstructive pulmonary disease (COPD), allergic asthma, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, or lung fibrosis.
 18. The compound for use according to any of claims 1 to 10 or the pharmaceutical composition for use according to claim 11 or the method of claim 12, wherein said inflammatory, autoimmune and/or allergic disorder is selected from rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, reactive arthritis, or polymyalgia rheumatica.
 19. The compound for use according to any of claims 1 to 10 or the pharmaceutical composition for use according to claim 11 or the method of claim 12, wherein said inflammatory, autoimmune and/or allergic disorder is selected from Guillain-Barre syndrome, Hashimoto's thyroiditis, Grave's disease, temporal arteritis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, or alopecia areata.
 20. The compound for use according to any of claims 1 to 10 or the pharmaceutical composition for use according to claim 11 or the method of claim 12, wherein said inflammatory, autoimmune and/or allergic disorder is selected from a graft-versus-host disease, a host-versus-graft disease or a transplant rejection.
 21. A compound of the following formula 3

wherein: R¹ is a C₁₀₋₂₀ hydrocarbon group; R² is a C₁₋₄ alkyl group, R³ is —H, a C₁₋₄ alkyl group or is absent, and R⁴ is —CH₂—CH(—OH)—CH₂— or a C₃₋₆ alkylene group, wherein said alkylene group is substituted with one or more groups independently selected from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH; or R² and R³ are mutually linked to form a pyrrolidine ring, a piperidine ring or an azepane ring together with the nitrogen atom X to which they are attached, wherein said pyrrolidine ring, said piperidine ring or said azepane ring is optionally substituted with one or more groups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or alkyl)(C₁₋₃ alkyl), and R⁴ is a C₃₋₆ alkylene group which is substituted with one or more groups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH; R⁵ is —SO₃ ⁻, —SO₃H, —PO₃H⁻, —PO₃ ²⁻, —PO₃H₂, —PO₂(OC₁₋₃ alkyl)⁻, —PO₂H(OC₁₋₃ alkyl), —PO(OC₁₋₃ alkyl)₂, —CO₂ ⁻, —CO₂H or —CO₂(C₁₋₃ alkyl); and X is N⁺ or, if R³ is absent, X is N; or a pharmaceutically acceptable salt, solvate or prodrug thereof for use as a medicament.
 22. The compound for use according to claim 21, wherein R⁵ is SO₃ ⁻ or SO₃H.
 23. The compound for use according to claim 21, wherein R⁵ is —PO₃ ²⁻, —PO₃H⁻, or —PO₃H₂.
 24. The compound for use according to any of claims 21 to 23, wherein R⁴ is —CH₂—CH(—R⁴¹)—CH₂— and R⁴¹ is selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH.
 25. The compound for use according to any of claims 21 to 24, wherein R¹ is a linear C₁₀₋₂₀ alkyl group, a linear C₁₀₋₂₀ alkenyl group, or a linear C₁₀₋₂₀ alkynyl group.
 26. The compound for use according to any of claims 21 to 25, wherein R¹ is —(CH₂)₁₁—CH₃, —(CH₂)₁₃—CH₃, or —(OH₂)₁₅—CH₃.
 27. The compound for use according to any of claims 21 to 26, wherein R² is methyl, and R³ is —H, methyl or R³ is absent.
 28. The compound for use according to any of claims 21 to 26, wherein R² and R³ are mutually linked to form a piperidine ring together with the nitrogen atom X to which they are attached, wherein the piperidine ring is optionally substituted with —OH.
 29. The compound for use according to claim 21, wherein the compound is a compound of the following formula 4

wherein: R¹ is a C₁₀₋₂₀ hydrocarbon group; R⁴ is a C₃₋₆ alkylene group which is substituted with one or more groups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH; R⁵ is —SO₃ ⁻, —SO₃H, —PO₃H⁻, —PO₃ ²⁻, —PO₃H₂, —PO₂(OC₁₋₃ alkyl)⁻, —PO₂H(OC₁₋₃ alkyl), —PO(OC₁₋₃ alkyl)₂, —CO₂ ⁻, —CO₂H or —CO₂(C₁₋₃ alkyl); each R⁶ is independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃ alkyl)(C₁₋₃ alkyl); n is 1, 2, or 3; and m is an integer from 0 to 4; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 30. The compound for use according to claim 21, wherein the compound is a compound of the formula 1a, 1b, 1c, 1d, or 1e

or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 31. A pharmaceutical composition comprising the compound of any of claims 21 to 30 and a pharmaceutically acceptable excipient.
 32. A method of treating, preventing or ameliorating a disease or disorder, the method comprising the administration of the compound of any of claims 21 to 30 or the pharmaceutical composition of claim 31 to a subject in need of such a treatment, prevention or amelioration.
 33. The compound of any of claims 21 to 30 or the pharmaceutical composition of claim 31 for use in the treatment, prevention or amelioration of an inflammatory, autoimmune and/or allergic disorder.
 34. A method of treating, preventing or ameliorating an inflammatory, autoimmune and/or allergic disorder, the method comprising the administration of the compound of any of claims 21 to 30 or the pharmaceutical composition of claim 31 to a subject in need of such a treatment, prevention or amelioration.
 35. The compound for use according to any of claim 1 to 10, 13 to 20 or 33 or the pharmaceutical composition for use according to any of claim 11, 13 to 20 or 33 or the method of any of claim 12 to 20 or 34, whereby said compound or said pharmaceutical composition is to be administered in combination with one or more immunomodulatory drugs and/or one or more anti-inflammatory drugs.
 36. The compound of any of claims 21 to 30 or the pharmaceutical composition of claim 31 for use in the treatment, prevention or amelioration of a proliferative, neoplastic or dysplastic disease or disorder.
 37. A method of treating, preventing or ameliorating a proliferative, neoplastic or dysplastic disease or disorder, the method comprising the administration of the compound of any of claims 21 to 30 or the pharmaceutical composition of claim 31 to a subject in need of such a treatment, prevention or amelioration.
 38. The compound for use according to claim 36 or the pharmaceutical composition for use according to claim 36 or the method of claim 37, wherein the proliferative, neoplastic or dysplastic disease or disorder is selected from leukemia, adrenocortical carcinoma, an AIDS-related cancer, appendix cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, breast cancer, a bronchial adenoma, Burkitt lymphoma, carcinoid tumor, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, colon cancer, cutaneous T-cell lymphoma, chronic lymphovytic leukemia, chronic myelogenous leukemia, a chronic myeloproliferative disorder, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, extracranial germ cell tumor, extrahepatic bile duct cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastric carcinoid, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, germ cell tumor, glioma, gestational trophoblastic tumor, head and neck cancer, heart cancer, hepatocellular cancer, Hodgkin lymphoma, Non-Hodgkin lymphoma, hypopharyngeal cancer, hypthalamic and visual pathway glioma, intraocular melanoma, islet cell carcinoma, Kaposi sarcoma, renal cell cancer, laryngeal cancer, lip and oral cavity cancer, lung cancer, Waldenstrom's macroglobulinemia, osteosarcoma, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, mouth cancer, multiple endocrine neoplasia syndrome, plasma cell neoplasm, mycosis fungoides, a myelodysplastic disease, multiple myeloma, a myeloproliferative disorder, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic tumor, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pineoblastoma, pituitary adenoma, pleuropulmonary blastoma, prostate cancer, rectal cancer, transitional cell cancer, rhabdomyosarcoma, salivary gland cancer, Szary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, supratentorial primitive neuroectodermal tumor, testicular cancer, throat cancer, thymoma, thyroid cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or Wilms tumor.
 39. The compound for use according to any of claim 1 to 10, 13 to 30, 33, 35, 36 or 38 or the pharmaceutical composition for use according to any of claim 11, 13 to 20, 33, 35, 36 or 38 or the pharmaceutical composition of claim 31 or the method of any of claim 12 to 20, 32, 34, 35, 37 or 38, whereby said compound or said pharmaceutical composition is to be administered by any one of: an oral route; topical route, including by transdermal, intranasal, ocular, buccal, or sublingual route; parenteral route using injection techniques or infusion techniques, including by subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intrasternal, intraventricular, intraurethral, or intracranial route; pulmonary route, including by inhalation or insufflation therapy; gastrointestinal route; intrauterine route; intraocular route; subcutaneous route; ophthalmic route, including by intravitreal, or intracameral route; rectal route; or vaginal route.
 40. The method of any of claims 12 to 20, 32, 34, 35 or 37 to 39, wherein said subject is a human.
 41. The method of any of claims 12 to 20, 32, 34, 35 or 37 to 39, wherein said subject is a non-human mammal.
 42. A compound of the following formula 5

wherein: R¹ is a C₁₀₋₂₀ hydrocarbon group; R² is a C₁₋₄ alkyl group, R³ is —H or is absent, and R⁴ is —CH₂—CH(—OH)—CH₂—; or R² is a C₁₋₄ alkyl group, R³ is —H, a C₁₋₄ alkyl group or R³ is absent, and R⁴ is a C₃₋₆ alkylene group which is substituted with one or more groups independently selected from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH; or R² and R³ are mutually linked to form a pyrrolidine ring, a piperidine ring or an azepane ring together with the nitrogen atom X to which they are attached, wherein said pyrrolidine ring, said piperidine ring or said azepane ring is optionally substituted with one or more groups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃ alkyl)(C₁₋₃ alkyl), and R⁴ is a C₃₋₆ alkylene group which is substituted with one or more groups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH; R⁵ is —SO₃ ⁻, —SO₃H, —PO₃H⁻, —PO₃ ²⁻, —PO₃H₂, —PO₂(OC₁₋₃ alkyl)⁻, —PO₂H(OC₁₋₃ alkyl), —PO(OC₁₋₃ alkyl)₂, —CO₂ ⁻, —CO₂H or —CO₂(C₁₋₃ alkyl); and X is N⁺ or, if R³ is absent, X is N; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 43. The compound of claim 42, wherein R⁵ is SO₃ ⁻ or SO₃H.
 44. The compound of claim 42, wherein R⁵ is —PO₃ ²⁻, —PO₃H⁻, or —PO₃H₂.
 45. The compound of any of claims 42 to 44, wherein R⁴ is —CH₂—CH(—R⁴¹)—CH₂— and R⁴¹ is selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH, or —O(CH₂)₃OH.
 46. The compound of any of claims 42 to 45, wherein R¹ is a linear C₁₀₋₂₀ alkyl group, a linear C₁₀₋₂₀ alkenyl group, or a linear C₁₀₋₂₀ alkynyl group.
 47. The compound of any of claims 42 to 46, wherein R¹ is —(CH₂)₁₁—CH₃, —(CH₂)₁₃—CH₃, or —(CH₂)₁₅—CH₃.
 48. The compound of any of claims 42 to 47, wherein R² is methyl, R³ is —H or is absent, and R⁴ is —CH₂—CH(—OH)—CH₂—.
 49. The compound of any of claims 42 to 47, wherein R² is methyl, R³ is —H, methyl or R³ is absent, and R⁴ is a C₃₋₆ alkylene group which is substituted with one or more groups independently selected from —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH.
 50. The compound of any of claims 42 to 47, wherein R² and R³ are mutually linked to form a piperidine ring together with the nitrogen atom X to which they are attached, wherein the piperidine ring is optionally substituted with —OH.
 51. The compound of claim 42, wherein the compound is a compound of the following formula 6

wherein: R¹ is a C₁₀₋₂₀ hydrocarbon group; R⁴ is a C₃₋₆ alkylene group which is substituted with one or more groups independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), —O—C(O)—O(C₁₋₃ alkyl), —O—C(O)—NH₂, —O—C(O)—NH(C₁₋₃ alkyl), —O—C(O)—N(C₁₋₃ alkyl)(C₁₋₃ alkyl), —O(CH₂)₂OH or —O(CH₂)₃OH; R⁵ is —SO₃ ⁻, —SO₃H, —PO₃H⁻, —PO₃ ²⁻, —PO₃H₂, —PO₂(OC₁₋₃ alkyl)⁻, —PO₂H(OC₁₋₃ alkyl), —PO(OC₁₋₃ alkyl)₂, —CO₂ ⁻, —CO₂H or —CO₂(C₁₋₃ alkyl); each R⁶ is independently selected from —OH, —O(C₁₋₃ alkyl), —O—C(O)—(C₁₋₃ alkyl), C₁₋₃ alkyl, —NH₂, —NH(C₁₋₃ alkyl) or —N(C₁₋₃ alkyl)(C₁₋₃ alkyl); n is 1, 2, or 3; and m is an integer from 0 to 4; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 52. The compound of claim 42, wherein the compound is a compound of the formula 1a, 1b, 1c, 1d, or 1e

or a pharmaceutically acceptable salt, solvate or prodrug thereof. 